The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index; 21 of the 33 sources its claims cite were checked for support.
Acquired Resistance to KRAS G12C Inhibition in Cancer
Open accessAbstract
BACKGROUND: ). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: inhibitors. RESULTS: inhibitors. CONCLUSIONS: inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).
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Claims the paper makes
21 of 33 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The mechanisms of acquired resistance to these therapies are currently unknown.”
- Also stated in: § CONCLUSIONS · plain
“Little is currently known about the clinical mechanisms of resistance to KRASG12C inhibition.6,7,15-17”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > BACKGROUND
What the sources say
- Not checked — no full text of the sourcecites [6] source
- Could not verifycites [7] sourceExperimental — accuracy not yet measured
The Results section on the CRISPR/Cas9 screen says KEAP1 loss may represent a mechanism of intrinsic or acquired resistance to MRTX849, but does not establish whether acquired-resistance mechanisms are currently unknown. The Discussion addresses transient or submaximal MRTX849 responses, not acquired resistance to both adagrasib and sotorasib. Searches for acquired resistance and sotorasib found no passage settling the claim. (LLM, conf=0.73)
- Could not verifycites [15] sourceExperimental — accuracy not yet measured
The Introduction and Discussion address rapid adaptive feedback resistance to KRASG12C inhibition, not whether mechanisms of acquired resistance to adagrasib and sotorasib are unknown. Searches for acquired resistance and long-term treatment found no passage addressing that specific claim; the indexed copy provides no page numbers. (LLM, conf=0.73)
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The opening Abstract says how cancer cells bypass KRASG12C inhibition was not understood. But the paper then identifies a mechanism of rapid adaptive escape; it does not establish that the mechanisms of acquired resistance to adagrasib and sotorasib remained unknown. Rapid escape shortly after treatment is not the same claim as acquired resistance to those therapies. (LLM, conf=0.80)
- Could not verifycites [17] sourceExperimental — accuracy not yet measured
The Introduction identifies EGFR reactivation as a mechanism of adaptive resistance to KRAS G12C inhibition in colorectal cancer. The Discussion says combination treatment could limit the emergence of acquired resistance, but does not state whether the mechanisms of acquired resistance to AMG510 (sotorasib) or MRTX849 (adagrasib) were known or unknown. No page numbers are available in our copy. (LLM, conf=0.72)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § CONCLUSIONS · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Despite the clinical benefit that was observed for many patients treated with KRASG12C inhibitors, acquired resistance to single-agent therapy eventually occurred in most patients.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > CONCLUSIONS
What the sources say
- Not checked — no full text of the sourcecites [6] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The Results section, “MRTX849 Antitumor Activity Translates to RECIST Responses in Cancer Patients” (page unavailable), reports clinical responses in two patients, both of whom remained on treatment at the reported follow-up. The Discussion describes a lack of durable regression in 9 of 26 tumor models, but does not establish that acquired resistance eventually occurred in most patients receiving single-agent therapy. (LLM, conf=0.87)
- Partly supportedcites [15] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) describes promising initial clinical activity with single-agent KRASG12C inhibition and says the durability of benefit may be limited. It does not report that most patients who benefited eventually developed acquired resistance; the clinical figure it gives is an initial response rate, not a rate of acquired resistance. (LLM, conf=0.87)
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The Abstract reports early partial responses in about 50% of lung cancer patients and describes rapid escape from inhibition in subsets of cancer cells. It does not report that acquired resistance eventually occurred in most patients receiving single-agent therapy; that clinical frequency and timeline are unsupported. (LLM, conf=0.87)
- Partly supportedcites [17] sourceExperimental — accuracy not yet measured
The Abstract reports clinical benefit for most patients with KRAS G12C-mutant NSCLC and limited response in colorectal cancer. The Introduction describes adaptive resistance in cell lines and patient-derived models, but our copy does not report that acquired resistance eventually occurred in most patients receiving single-agent therapy. (LLM, conf=0.86)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery source the paper cites for this claim was checked and supports it.
In the paper
“These resistance mutations probably increase the fraction of KRAS protein in the active GTP-bound form that does not bind to the drug.4”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
What the sources say
- Supportedcites [4] source
The paper reports that mutations impairing GTPase activity or increasing nucleotide exchange reduce sensitivity to ARS853. It explains that ARS853 preferentially binds GDP-bound KRASG12C, while increased exchange lowers the amount of GDP-bound protein available for drug binding (passages 4, 7). This supports the citing sentence’s proposed mechanism. (LLM, conf=0.91)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In recent work, a case was described of an acquired Y96D switch II pocket mutation identified at a low variant allele frequency in ctDNA at the time of acquired resistance to adagrasib.23”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
What the sources say
- Supportedcites [23] source
The Results section reports a patient who developed acquired resistance to MRTX849 (adagrasib) and whose post-progression cell-free DNA contained emerging mutations at lower allele frequencies than the original mutations. It identifies KRAS Y96D among those mutations and places Y96 in the switch-II pocket. Page numbers are not available in our copy. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In several patients, multiple mechanisms of resistance were identified simultaneously through ctDNA analysis”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“several mutations that were associated with resistance to both drugs were detected in amino acids located outside the drug-binding pockets of adagrasib and sotorasib, including known oncogenic mutations at codons 13, 59, 61, 117, and 146 that impede GTP hydrolysis or promote GDP-to-GTP nucleotide exchange”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > RESISTANCE MUTATIONS REVEALED BY DEEP MUTATIONAL SCANNING
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In 1 patient, the G12C-mutant codon 12 (c.34G→T) apparently acquired an additional mutation (c.36T→G), leading to a mutation from cysteine to tryptophan (c.34_36 GGT→TGT→TGG, ultimately noted as a G12W mutation) (Fig. 1C and Fig. S2B), which conferred resistance to adagrasib.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additional strong MRTX1257-resistance mutations were detected at codons 8, 9, 64, 99, and 117.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > RESISTANCE MUTATIONS REVEALED BY DEEP MUTATIONAL SCANNING
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Putative mechanisms of resistance to adagrasib were identified in 17 of 38 patients (45%).”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The putative resistance mechanisms identified in post-progression samples are causally responsible for clinical resistance to adagrasib.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Multiple mutations that were identified in the screen at codons 12, 68, 95, and 96 conferred strong resistance to MRTX1257.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > RESISTANCE MUTATIONS REVEALED BY DEEP MUTATIONAL SCANNING
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 28
- The quote only partly states this claim. 1
- Probably not a substantial claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“compounds have been identified that bind covalently to cysteine 12 within the switch II pocket of the GDP-bound form of the KRASG12C protein, preventing oncogenic signaling and causing potent tumor regressions in preclinical models.3-7”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > CONCLUSIONS
What the sources say
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
The paper’s structural and cellular-results passages support covalent binding at cysteine 12 in the switch-II pocket of GDP-bound KRAS(G12C) and impaired signaling-related interactions. They do not support potent tumor regressions in preclinical models: the reported effects are in lung cancer cell lines, and the discussion says the compounds require further optimization before in vivo assessment. The relevant passages have no page numbers in our copy. (LLM, conf=0.91)
- Partly supportedcites [4] sourceExperimental — accuracy not yet measured
The paper’s main text (indexed under Abstract; page unavailable) reports that ARS853 preferentially binds GDP-bound KRASG12C and suppresses KRAS-GTP and downstream signaling in mutant lung cancer cells. The passages do not establish covalent binding specifically to cysteine 12 in the switch II pocket, and they report cell-line growth inhibition and apoptosis—not potent tumor regressions in preclinical models. (LLM, conf=0.88)
- Supportedcites [5] sourceExperimental — accuracy not yet measured
The Introduction describes covalent binding to Cys-12 in the switch II pocket of GDP-bound KRASG12C. The Results report that ARS-1620 selectively inhibits RAS signaling in KRASG12C cells and produces marked tumor regression in mouse xenograft models. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [6] source
- Supportedcites [7] sourceExperimental — accuracy not yet measured
The Introduction describes covalent binding at KRASG12C cysteine 12, an exploitable pocket beneath switch II, stabilization of the inactive GDP-bound form, and inhibition of KRAS-dependent signaling. The Results section on xenograft models reports substantial tumor regression with MRTX849 in 17 of 26 preclinical models. Page numbers are unavailable in our copy. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In early-phase clinical trials, two potent, selective, and irreversible small-molecule KRASG12C inhibitors have shown promising results in non–small-cell lung cancer (NSCLC) and more modest efficacy in colorectal cancer: adagrasib (MRTX849) and sotorasib (AMG510).6,7,10”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > CONCLUSIONS
What the sources say
- Not checked — no full text of the sourcecites [6] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The Results section on responses in cancer patients reports partial responses to MRTX849 (adagrasib) in one lung adenocarcinoma patient and one colorectal cancer patient enrolled in a phase 1b trial. It does not establish that efficacy was more modest in colorectal cancer, and the passages found do not report clinical results for sotorasib (AMG510). Page numbers were not available in our copy. (LLM, conf=0.86)
- Supportedcites [10] sourceExperimental — accuracy not yet measured
The Results (Efficacy) describe this phase 1 sotorasib trial and report confirmed responses in 32.2% of patients with NSCLC versus 7.1% of patients with colorectal cancer. That supports the attributed contrast for sotorasib; this paper is not the evidence for adagrasib, which the sentence cites alongside it. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Sotorasib was associated with an objective response rate of 37.1% and a median progression-free survival of 6.8 months among patients with NSCLC14 and a response rate of 7.1% among those with colorectal cancer.10”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > CONCLUSIONS
What the sources say
- Supportedcites [14] source
The citation to this paper is attached to the NSCLC results, not the separately cited colorectal-cancer result. In Results > Efficacy, the paper reports an objective response rate of 37.1% and median progression-free survival of 6.8 months among patients with previously treated KRAS p.G12C–mutated NSCLC. (LLM, conf=0.95)
- Supportedcites [10] source
The citation to this paper is attached to the colorectal-cancer response rate, not the NSCLC figures. The Results > Efficacy > Colorectal Cancer passage reports a confirmed partial response in 3 of 42 patients (7.1%). (LLM, conf=0.95)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“An ongoing phase 1–2 study of adagrasib that involves patients with KRASG12C-mutant cancer has shown an objective response rate of 45% among patients with NSCLC11,12 and 17% among those with colorectal cancer.13”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > CONCLUSIONS
What the sources say
- Supportedcites [11] source
The KRYSTAL-1 Methods and Results passage describes a phase I/II adagrasib study and reports partial responses in 45% (23/51) of patients with evaluable NSCLC. The colorectal-cancer figure has a separate citation in the citing sentence and is not attributed to this source. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [12] source
- Not checked — no full text of the sourcecites [13] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In two patients with NSCLC for whom we were not able to identify a genomic resistance mechanism, we observed histologic transformation from adenocarcinoma to squamous-cell carcinoma, which suggests that nongenetic mechanisms of resistance to KRASG12C inhibition may occur, similar to those observed with other targeted therapies in lung cancer.24-26”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [24] source
- Supportedcites [25] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [26] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ba/F3 cells that express KRASG12C are highly sensitive to treatment with either adagrasib or sotorasib and show dose-dependent inhibition of downstream KRAS effector signaling”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > ROLE OF DRUG-BINDING SITE MUTATIONS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“expression of the G12C/R68S and G12C/Y96C double mutants mediated resistance to sotorasib; in contrast, the G12C/H95D, G12C/H95Q, and G12C/H95R mutants remained sensitive to sotorasib”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > ROLE OF DRUG-BINDING SITE MUTATIONS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A total of 38 patients treated with adagrasib who initially had stable disease for at least 12 weeks or an objective response to therapy followed by subsequent disease progression were included in this study: 27 patients had NSCLC, 10 had colorectal cancer, and 1 had appendiceal cancer.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > RESULTS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At the time of acquired resistance to adagrasib, tissue was available for analysis for 10 patients, and ctDNA was available for 32 patients; both tissue and ctDNA were obtained from 4 of these patients.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Strength:plain· not yet calibratedn = 32Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Pathogenic mutations in other receptor tyrosine kinase (RTK)–RAS–MAPK pathway members were also detected in patients with acquired resistance to adagrasib, including NRAS (Q61K in one patient), BRAF (V600E in two patients), MAP2K1/MEK1 (K57T in one patient, K57N in two patients, an I99_K104 deletion in one patient, and an E102_I103 deletion in two patients), and EGFR (A289V in one patient)”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the Y96C drug-binding resistance mutation showed high-level resistance to both inhibitors, whereas the H95D, H95Q, and H95R mutations caused resistance to adagrasib but not to sotorasib.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > RESISTANCE MUTATIONS REVEALED BY DEEP MUTATIONAL SCANNING
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > RESULTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biochemical analysis of the response to adagrasib in Ba/F3 cells showed that the R68S, H95D/Q/R, and Y96C second-site mutations in KRASG12C blocked drug binding, as indicated by the absence of KRAS band shift mediated by covalent drug binding, and completely prevented the drug-mediated suppression of RAS–MAPK signaling, as measured by sustained phosphorylated extracellular signal-regulated kinase”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > ROLE OF DRUG-BINDING SITE MUTATIONS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Novel acquired secondary KRAS mutations within the adagrasib-binding pocket were found in 4 patients, including a Y96C mutation in 1 patient with NSCLC (Fig. 1A and Fig. S1), H95Q and H95R mutations in 1 patient with colorectal cancer (Fig. 1B), R68S and H95D mutations in 1 patient with NSCLC (Fig. 1C), and an H95R mutation in another patient with colorectal cancer (Fig. 1D).”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A comparison of resistance patterns between MRTX1257 and sotorasib showed generally strong concordance, although several drug-specific resistance mutations were identified.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > RESISTANCE MUTATIONS REVEALED BY DEEP MUTATIONAL SCANNING
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“multiple resistance mechanisms appeared to be more common in colorectal cancer; among patients with available ctDNA sequencing, 4 of 5 patients with colorectal cancer and 2 of 7 patients with NSCLC had multiple resistance alterations, although this difference was not significant.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > MECHANISMS OF ACQUIRED RESISTANCE TO ADAGRASIB
Strength:hedged· not yet calibratedn = 7Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Five patients acquired codon 12 KRAS mutations that prevent adagrasib binding, and other secondary mutations in the switch II drug-binding pocket were observed in 4 patients (11% of the entire cohort) at the R68, H95, and Y96 positions.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We performed DNA sequencing of tumor-biopsy samples or ctDNA from 38 patients with acquired resistance to adagrasib and described putative mechanisms of resistance for 17 patients (45%) that can be classified into three main categories.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
- Rests on an assumption: The putative resistance mechanisms identified in post-progression samples are causally responsible for clinical resistance to adagrasib.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we identified additional second-site resistance mutations at oncogenic hotspots that cause decreased GTP hydrolysis (e.g., G13D and Q61R) or enhanced GDP-to-GTP nucleotide exchange (e.g., G13D, A59S, and A146P).”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the H95 adagrasib-specific resistance mutations occurred in a small number of patients (3 of 38), and each coevolved with multiple other alterations that would confer strong resistance to both adagrasib and sotorasib.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our cohort, multiple genomic alterations within the same patient, as well as acquired gene fusions, appeared to be more prevalent in colorectal cancer than in NSCLC.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C).”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > Abstract > BACKGROUND
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“mapping of these same residues onto the x-ray crystallographic structure of sotorasib bound to the KRASG12C protein (6OIM)6 suggested strong interactions of R68 and Y96 with sotorasib but probably weaker interactions with the H95 residue, although additional studies would be needed to quantify the strength of these interactions”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > ROLE OF DRUG-BINDING SITE MUTATIONS
What the sources say
- Not matchedcites 6OIM
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [6] source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“7 of 17 patients (41%) had more than one concurrent potential resistance mechanism identified, which suggests that irreversible covalent inhibition of KRASG12C leads to strong selective pressures and convergent evolution of multiple distinct mechanisms of resistance.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that the tumor and ctDNA sequencing performed on these specimens did not miss a major known molecular driver of adagrasib resistance, but it remains possible that more extensive genomic sequencing of these samples could identify other acquired alterations that may have contributed to resistance.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Although the Y96C mutation appeared to be a clonal resistance event, the R68S and H95D/Q/R secondary KRAS mutations were identified in ctDNA at relatively low variant allele frequency as compared with that of the KRASG12C allele and occurred in the presence of other concurrent resistance mutations, which suggests subclonality or heterogeneity of these mutations across each patient’s burden of dise”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
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“The heterogeneous nature of the tumor and ctDNA sequencing platforms that were used to characterize acquired resistance is a limitation of this study.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
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In the paper
“This study focused on acquired resistance mechanisms in patients treated with adagrasib and did not evaluate patients treated with sotorasib.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > DISCUSSION
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In the paper
“In summary, deep mutational scanning has defined the landscape of KRAS mutations that cause resistance to KRASG12C inhibitors. These studies identified distinct mechanistic classes of resistance mutations as well as drug-specific resistance patterns.”
§ Acquired Resistance to KRASG12C Inhibition in Cancer > RESULTS > RESISTANCE MUTATIONS REVEALED BY DEEP MUTATIONAL SCANNING
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The putative resistance mechanisms identified in post-progression samples are causally responsible for clinical resistance to adagrasib.
“Putative mechanisms of resistance to adagrasib were identified in 17 of 38 patients (45%).”
“Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors”
The paper relies on this without support.
The resistance mechanisms observed in the 38 KRYSTAL-1 patients are representative of acquired resistance to adagrasib in KRASG12C-mutant cancers generally.
“Among patients with KRASG12C-mutant cancers treated with adagrasib monotherapy in the KRYSTAL-1 trial, we performed histologic and genomic analyses of samples obtained at the time of disease progression to identify mechanisms of resistance to adagrasib.”
“KRASG12C-mutant cancers appear to evolve diverse mechanisms of resistance to adagrasib.”
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Emerging data suggest that potential mechanisms of acquired resistance to KRAS G12C inhibitors in colorectal cancer largely include reactivation of MAPK signaling, and future analyses from this trial and others will help to clarify these mechanisms.37”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C (2023) · cites this paper as [37]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite the established role of lineage plasticity in resistance to KRAS-targeted therapies,26–31 effective therapeutic interventions targeting drivers of lineage plasticity remain lacking.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [27]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous reports have shown that PIK3CA mutations can confer acquired resistance to KRAS G12C inhibitor and KRAS G12C inhibitor–cetuximab combination therapy in patients with NSCLC and CRC34–36.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [36]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The discovery of KRAS G12C inhibitors raises great excitement; nevertheless, intrinsic and acquired resistance to sotorasib and adagrasib has been reported in preclinical studies and clinical trials (8–10).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It is believed that this resistance can arise from a variety of mechanisms, including the emergence of additional mutations in KRAS or other genes involved in the RAS pathway, non-mutational activation of bypass signaling pathways such as the MAPK or PI3K pathways, and diverse remodeling of the tumor microenvironment (8–10).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [8]
Experimental — accuracy not yet measured
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In the citing paper
“One major route leading to such recovery of RAS activity is the activation of RTKs through either genetic (e.g., gene amplification or fusion) or non-genetic mechanisms.2,4,5,6,7,8,22,23,24,25”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Expression of the identified KRAS mutants was sufficient to confer resistance to KRAS G12C inhibitors in KRAS G12C cancer cells [49, 51, 60].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Similarly, a higher frequency of genetic alterations was identified by ctDNA analysis in adagrasib-treated CRC patients (4/5) than NSCLC patients (2/7) [49].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Acquired mutations of NRAS, BRAF, RTK, and MYC were also found in patients treated with sotorasib or adagrasib monotherapy [49, 51, 53, 54].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These results indicate the rapid development of acquired resistance to KRAS G12C inhibitors [18, 26, 27, 49].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Amplifications or gene fusions of MET, EGFR, FGFR2, FGFR3, and ALK have been detected in patients with acquired resistance to sotorasib and adagrasib monotherapy [49, 51].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Therapeutic pressure from KRAS inhibition can rapidly reshape tumor clonal architecture [35,36,47,81].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [35]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Point mutations in the KRAS gene included G12D/F/R/V/W, which prevent covalent interactions with mutant cysteine, as well as V8L, G13D, V14I, Q61H, H95D/Q/R, Y96C, and Y96D [62,97,102,103].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [102]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These included ALK, APC, CDKN2A/B, CTNNB1, IDH1/2, KEAP1, MET, MYC, NRAS, PTCH1, PTEN, RB1, RET, RICTOR, SMARCA4, and TP53 [50,97,102].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [102]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In KRAS inhibitor-resistant tumors, genetic alterations observed in upstream regulators included transmembrane growth factor receptors EGFR and FGFR2/3 as well as the KRAS-regulating GAP protein NF1 [102].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [102]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Multiple mechanisms of acquired resistance have been identified, which largely converge on re-activation of the RAS pathway or alternatively activate parallel signaling pathways such as the PI3K/mTOR pathway10–14.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We and others have recently described mechanisms of acquired resistance in patients with lung and colorectal cancer (CRC) treated with KRASG12C inhibitors, including mutations in KRAS or other RTK–RAS–MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states (14, 18–24).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Lineage plasticity has emerged as a critical mechanism of non-genetic resistance to KRAS-targeted therapies in NSCLC and PDAC.27–31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [27]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent studies using preclinical models have indicated that acquired resistance to KRASG12C inhibition may be mediated by the activation of multiple receptor tyrosine kinase (RTK) regulators, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin-like growth factor 1 receptor (IGF1R), human epidermal growth factor 2 (HER2), and Src homology 2 domain-”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Vertical reactivation of the RAS pathway elements has been observed in most samples collected from patients who developed resistance to KRASG12C inhibitors.4,8,20,21”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Even in NSCLC patients, the response to KRAS G12C inhibitors was often short-lived, with a DOR of 10.9–11.1 months and PFS of 6.3–6.8 months for sotorasib, and a DOR of 8.5 months and PFS of 6.5 months for adagrasib (Table 1).”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Genetic alterations, especially secondary RAS mutations, have been identified as one of the most common mechanisms of acquired resistance to KRAS inhibitors in patients [49, 51–55].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, clinical efficacy remains limited by intrinsic and acquired resistance, adaptive pathway reactivation, and tumor heterogeneity.”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [35]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, a significant challenge with KRAS inhibitors is that the majority of patients do not respond to such treatments, and initial responders will inevitably encounter disease progression. 9-12”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [9]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The co-evolution of multiple putative drug-resistance mechanisms within the same tumors mirrors observations in human samples whereby multiple distinct mechanisms have been observed within the same patients (14, 18, 19).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“Although this is an important milestone in precision oncology, G12Ci treatments are facing challenges due to the emerging development of drug resistance (13, 14).”
From SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition (2024) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Various putative mechanisms of resistance have been identified, including both on-target and off-target mechanisms that can confer resistance to KRAS-G12Ci (13).”
From SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition (2024) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Similarly, secondary KRAS mutations (G12D, G12R, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, and Y96C) and gene amplifications were detected in 9 out of 38 (27 NSCLC, 10 CRC, and 1 other) patients treated with adagrasib through the analysis of tumor tissues or circulating tumor DNA (ctDNA) [49].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“Inactivating mutations in PTEN were detected in KRAS G12C patients with acquired adagrasib resistance [49].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“This mutation was previously identified to confer resistance to both sotorasib and an analog of adagrasib when occurring in cis with the G12C mutation (18).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“Differentiation into alveolar type 1 (AT1)-like,26 squamous,27,28 as well as mucinous states29 has been implicated to contribute to KRAS inhibitor tolerance in lung adenocarcinoma, whereas transition into a classical state is observed in PDAC cells surviving KRAS-targeted therapy.30,31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [27]
The cited source says what the claim attributes to it.
In the citing paper
“In NSCLC, KRAS-mutant tumors evade therapy through transition into AT1-like,29 squamous,27,28 or mucinous states,29 while pancreatic cancer cells adopt a classical epithelial state to bypass KRAS inhibition.30,31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [27]
The cited source says what the claim attributes to it.
In the citing paper
“Upon disease progression with divarasib plus cetuximab, the majority (92.9%) of patients profiled had at least one genomic alteration that may be associated with treatment resistance similarly to two previous reports26,27, which is higher than that of patients treated with divarasib (30.2%) or other KRAS G12C inhibitors as single agent11,28,29.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, the therapeutic response to KRAS G12C inhibition was short-lived, with quick emergence of acquired resistance.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“emergence of acquired resistance limits further clinical benefit (28)”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“Although recent clinical trials of KRASG12C inhibition have shown modest efficacy in KRASG12CMT colorectal cancer”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“Prior studies indicated that tumors with acquired resistance to KRASG12C agents can have multiple resistance mechanisms, including alterations within the RAS/MAPK pathway and bypass activating alterations”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“this is consistent with analysis of clinical samples from patients treated in phase I/II studies with adagrasib”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [28]
In the citing paper
“Sensitivity for KRAS G12C detection at baseline for Cohort A patients with a confirmed KRAS G12C mutation by tumor tissue test was 75.5% (40/53)”
From Early Changes in Circulating Cell-Free KRAS G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients (2023) · cites this paper as [23]
In the citing paper
“Nonetheless, there remains an ongoing need for improved clinical outcomes (21), especially since emerging data indicate multiple mechanisms of acquired resistance in patients treated with sotorasib or adagrasib (22–24), many of which involve RAS pathway reactivation.”
In the citing paper
“By contrast, the G12C/H95D, G12C/H95Q and G12C/H95R double mutants remained sensitive to sotorasib”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [106]
In the citing paper
“Awad et al.106 studied baseline and post-treatment samples from 38 patients who developed resistance to adagrasib and found alterations suggestive of various mechanisms of resistance in 17 (45%).”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [106]
In the citing paper
“suggesting the potential for benefit from this agent in some patients with resistance to adagrasib”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [106]
In the citing paper
“These alterations included secondary KRAS mutations (G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R or Y96C) in nine patients (23%)”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [106]
In the citing paper
“Notably, in vitro validation studies confirmed that R68S, H95D/Q/R and Y96C second-site mutations affecting the switch 2 pocket of KRASG12C result in resistance to adagrasib106.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [106]
In the citing paper
“Of note, this compound is also active against ‘RAS oncogene switch’ mutations (within the switch 2 pocket), which confer resistance to adagrasib106, and it shows synergy with anti-PD-1 antibodies185.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [106]
In the citing paper
“Preclinical and clinical studies, however, have demonstrated that cancers lose sensitivity to KRASG12Ci and re-establish RAS-MAPK signaling through multiple mechanisms, including increased activation of mutant or wild-type (WT) RAS and/or gain of upstream/downstream bypass events1,7,9,10,13,14.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [9]
In the citing paper
“Despite this success, disease progression occurs in many patients4,5,7, with development of resistance to KRASG12Ci recapitulated in preclinical studies9–11.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [9]
In the citing paper
“Transcriptomic analysis of tumors explanted at the end of study, however, did not identify secondary KRAS mutations, increased KRAS expression, or genomic aberrations, previously reported in tumors with acquired resistance to KRASG12Ci (refs. 9,11) (Supplementary Table 12).”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [9]
In the citing paper
“Long-term culture in high-dose adagrasib (10 × IC50) was used to generate adagrasib-resistant NCI-H358 cells (NCI-H358R), which were confirmed to retain KRASG12C and did not acquire any mutations associated with resistance in patients9,11 (Supplementary Table 10).”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [9]
In the citing paper
“Pan-KRAS drugs would have advantages versus mutant-selective KRAS drugs in heterogeneous cancers driven by multiple KRAS alterations at baseline or upon development of acquired resistance due to secondary KRAS on-target alterations when compared to mutant-selective inhibitors (Fig. 3), with first examples emerging in the clinic (64–66).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“Importantly, additional clinical data may be able to address the question what drives therapy resistance in more than half of the patients (21 of 38) that harbored no identifiable molecular or histological alterations upon progression on adagrasib (64).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“Importantly, nine of 17 patients (53%) with detected putative resistance mechanisms harbored a least one acquired KRAS alteration.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“The vast majority of these patients (15 of 17) acquired molecular alterations leading to reactivation of RAS/MAPK signaling, albeit with the majority at low allelic frequencies, while in most cases maintaining the KRAS G12C mutated allele.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“Differential preclinical profiling of sotorasib and adagrasib revealed specific secondary KRAS mutations that elicit resistance to one drug but maintain sensitivity to the other (64, 95), e.g. KRASG12C harboring additional mutations in the position H95, such as H95D/Q/R, abrogated the activity of adagrasib but remained vulnerable to sotorasib.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“Identified putative resistance mechanisms include on-target and beyond-target alterations (Fig. 4) and fall into six different classes:”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“Furthermore, seven of 17 patients (41%) acquired more than one putative resistance mechanism, a finding that appeared more prevalent in CRC than NSCLC patients.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [64]
In the citing paper
“Preclinical and clinical data suggest that resistance to KRAS p.G12C inhibition is dependent on receptor tyrosine kinase activity, especially epidermal growth factor receptor (EGFR)-signalling.29 31 32”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [29]
In the citing paper
“An overall response rate (ORR) of only 7.1% and median progression-free survival (mPFS) of 4.0 months were observed in the group of patients with mCRC.29 30”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [29]
In the citing paper
“In terms of secondary mutations in the target gene, mutations in H95 and Y96, which are the key binding sites on mutant KRAS for the inhibitors, are most common [74].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [74]
In the citing paper
“Structural analyses suggest that adagrasib interacts with all three residues, while sotorasib primarily interacts with R68 and Y96, forming weaker bonds with H95 [74].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [74]
In the citing paper
“Sotorasib and adagrasib both form covalent bonds with KRASG12C, enhancing their binding affinity via non-covalent interactions with R68, H95, and Y96.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [74]
In the citing paper
“In an analysis of 38 patients with KRAS G12C cancers treated with adagrasib monotherapy, including 27 with NSCLC and 10 with colorectal cancer, mechanisms of acquired resistance were identified in 45% [113].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [113]
In the citing paper
“correlative studies conducted in other KRASG12C-mutant tumor types treated with these inhibitors have demonstrated the emergence of pleiotropic resistance through both cell autonomous and non-cell autonomous mechanisms76–78.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [78]
In the citing paper
“Awad et al. also observed some patients with high-level focal amplifications of the KRAS (G12C) allele [94].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“Awad et al. generated Ba/F3 cell lines with G12C/R68S, G12C/H95D, G12C/H95Q, G12C/H95R and G12C/Y96C double-mutant alleles and observed a marked resistance to MRTX849 in these cell lines [94, 95].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“KRAS mutations, including G13D, A59S, K117N, and A146P, that are outside the drug-binding pocket and correlated with enhanced nucleotide exchange, are associated with milder drug resistance than G12R and Y96C mutations.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“These mutations may increase the portion of the active KRAS in a GTP-bound state that does not bind the drugs [94] (Fig. 3).”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“Dual MET/KRAS (G12C) inhibition resulted in tumor shrinkage in AMG510-resistant xenograft mice [94, 113].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“For instance, BRAF (V600E) and MAP2K1/MEK1 (K57T, K57N, I99_K104 deletion, and E102_I103 deletion) can also cause acquired drug resistance [94, 108–111].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“Similar phenomenon occurs in other targeted therapies for lung cancer [94, 140, 141].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“Awad et al. found that tumor cells of 2 out of 10 patients (9 with NSCLC and 1 with CRC) transformed from adenocarcinoma to squamous cell carcinoma during MRTX849 treatment without any other identifiable drug resistance mechanisms [94].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“In phase I/II clinical trials (NCT03785249), three out of the five NSCLC patients achieved a PR, and one of two patients with CRC patients achieved a PR [94].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“For example, oncogene rearrangements, including EML4-ALK and CCDC6-RET, have been reported in three CRC patients treated with MRTX849 [94].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“In preclinical studies, possible resistance mechanisms for KRAS mutation therapy include secondary mutations in the KRAS binding site, reactivation of multiple upstream and downstream effectors, cell-cycle dysregulation, and immune deficiency [94, 95].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [94]
In the citing paper
“Noteworthy, DMS strategies have previously been successfully employed to investigate functional relationships between small molecules and target proteins31,32.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [32]
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Unraveling the Impact of KRAS Accessory Proteins on Oncogenic Signaling Pathways
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Sensitization Strategies for Drug Therapy in KRAS-Mutant Colorectal Cancer
孟, 秋. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.162386
Fowler, C. E., O’Hearn, N. A., Henning, N., Griffen, A. J., Ye, Z., Mathey‐Andrews, N., Salus, G., Hazan, R., Jacks, T., Burds, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.30.702866
“Since LUAD can transdifferentiate to squamous or neuroendocrine states 38–43 , we also screened for relevant markers, but observed no significant changes ( Supplementary Fig.”
Third-line and beyond treatment in mCRC and sequencing
Maurel, J., & Piedra, M. R. (2026) · Revisiones en cáncer · doi:10.20960/revcancer.00130
Design, synthesis and biological evaluation of novel KRAS-G12D inhibitors
Baig, M. H., Jo, Y. S., Nale, S. D., Kim, C. J., Park, J., Ha, J., Moon, B., Ryu, S., & Dong, J.-J. (2026) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2025.2609342
Liu, M., Luo, K., Song, Y., Cai, Y., Zhao, H., Zhao, Y., Ma, D., & Zhang, H. (2026) · Medical Oncology · doi:10.1007/s12032-026-03248-z
Biología molecular del cáncer de pulmón de célula no pequeña
Zuluaga, J. A., Rojas, L., Arrieta, O. G., Corrales, L., Ruíz-Patiño, A., Viola, L., Martínez, S., Carvajal, C. A., González, A., Zuluaga, C., et al. (2026) · Revista Colombiana de Hematología y Oncología · doi:10.51643/22562915.838
Targeting SHOC2: a treatable therapeutic site in RAS(Q61) mutant cancers
Tang, J., Ding, G., & Zhang, J. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3077-6
Gentile, C., Feng, W. W., Lenahan, S. M., Ying, A. W., Card, D. C., Wu, F. T. H., Pham, N., Radulovich, N., Cao, P. M., Hueniken, K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.27.708377
Frisch, A., Martin, E., Cannon, T. L., Wadlow, R. C., Raghavan, S., Sen, T., & Karim, N. A. (2026) · Current Oncology · doi:10.3390/curroncol33030148
“Off-state inhibitors rely on nucleotide cycling and may lose efficacy in tumors favoring persistent GTP-bound KRAS or altered upstream flux [11,22].”
InfluentialAn evolving landscape: predictive and therapeutic biomarkers in advanced non-small cell lung cancer
Fortman, D. D., & Qin, A. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1750153
“…and an increased copy number confers a worse prognosis in NSCLC (150 – 152); additionally, MET ampli fi cation has been implicated in bypass mechanisms of resistance to KRAS G12C inhibitors and in a minority of patients treated with selpercatinib in RET-fusion positive advanced NSCLC (153, 154).”
Constitutive EGFR Activation Induced by PTPRR Downregulation Confers Resistance to KRAS Inhibitors
Kanemura, H., Takehara, T., Maenishi, O., Tomida, S., Iwawaki, N., Kunimasa, K., Nakayama, T., Watanabe, S., Suzuki, S., Sakai, K., et al. (2026) · Cancer Research Communications · doi:10.1158/2767-9764.crc-25-0489
Luo, G., Li, D., Peng, J., Liu, R., Meng, Y., Ward, R., Zhang, Y., Zhang, X., Cui, F., Wang, J., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-02798-z
Self-citationWang, J., Yan, Y., Su, Q., & Jia, Y. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1776402
Metadata
- Authors
- Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., Jacobson, J. O., Yang, X., Persky, N. S., Root, D. E., Lowder, K. E., Feng, H., Zhang, S. S., Haigis, K. M., Hung, Y. P., Sholl, L. M., Wolpin, B. M., Wiese, J., Christiansen, J., Lee, J., Schrock, A. B., Lim, L. P., Garg, K., Li, M., Engstrom, L. D., Waters, L., Lawson, J. D., Olson, P., Lito, P., Ou, S.-H. I., Christensen, J. G., Jänne, P. A., & Aguirre, A. J.
- Affiliations
- Broad Institute (US)
- From Dana–Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women’s Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge — all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) — all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-06-24
- Volume
- 384
- Issue
- 25
- Pages
- 2382-2393
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC8864540
- OpenAlex
- W3174662367
- Semantic Scholar
- 01a72070b1162777632d392aa5d2ffd80998f017
- Cited by
- 1,247
- References
- 26
- Citations by year
- 2026: 249 · 2025: 290 · 2024: 285 · 2023: 211 · 2022: 164 · 2021: 48
- FWCI
- 116.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (1R01CA230267-01A1, 1R01CA230745-01, K08 CA218420-02, P50 CA127003, U01 CA210171)
- American Cancer Society (CRP-17-111-01-CDD)
- Mark Foundation for Cancer Research (19-029 MIA)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12C, acquired drug resistance, KRAS inhibitors, cancer therapy resistance, KRAS mutation, resistance mechanisms
- MeSH terms
- Acetonitriles, Appendiceal Neoplasms, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Protein Conformation, Pyridines, Pyrimidines, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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