Diverse alterations associated with resistance to KRAS(G12C) inhibition
Open accessAbstract
Inactive state-selective KRAS(G12C) inhibitors 1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer 9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.
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Intrinsic and acquired resistance to sotorasib and adagrasib has been reported in preclinical studies and clinical trials.
“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 [9]
The paper reports treatment-emergent alterations in patients treated with sotorasib (Abstract; no page given) and acquired resistance to both sotorasib and adagrasib in preclinical models (Methods and Extended Data; no pages given). It also notes baseline KRAS amplification in models with weaker treatment responses. It does not report clinical resistance to adagrasib, so the claim is broader than this source supports. (LLM, conf=0.88)
Experimental — accuracy not yet measuredResistance to KRAS G12C inhibitors can arise from additional mutations in KRAS or other RAS pathway genes, non-mutational activation of bypass signaling pathways such as MAPK or PI3K, and remodeling of the tumor microenvironment.
“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 [9]
The paper reports treatment-emergent KRAS, NRAS, and BRAF mutations and shows that secondary RAS mutations can bypass KRAS(G12C) inhibition by reactivating ERK signaling (Abstract; page unavailable). It does not establish the claimed non-mutational activation of MAPK or PI3K bypass pathways or tumor-microenvironment remodeling as resistance mechanisms. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAcquired mutations of NRAS, BRAF, RTK, and MYC were found in patients treated with sotorasib or adagrasib monotherapy.
“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 [51]
The clinical-results passage (indexed under Abstract; page unavailable) reports treatment-emergent NRAS and BRAF mutations and EGFR and FGFR2 alterations in patients treated with sotorasib. It identifies the MYC alteration as amplification, not a mutation. The Patient specimens section describes a sotorasib-treated cohort; adagrasib was tested in models, not in this patient cohort. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAmplifications or gene fusions of MET, EGFR, FGFR2, FGFR3, and ALK have been detected in patients with acquired resistance to sotorasib and adagrasib monotherapy.
“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 [51]
The clinical-results passage (indexed under Abstract; page unavailable) reports treatment-emergent MET, EGFR, and FGFR2 amplifications in patients treated with sotorasib. It does not report FGFR3 or ALK amplifications or gene fusions in those patients. The Methods: Patient specimens section specifies sotorasib treatment; adagrasib appears in the supplied passages only in preclinical models, not the patient cohort. (LLM, conf=0.90)
Experimental — accuracy not yet measuredExpression of the identified KRAS mutants was sufficient to confer resistance to KRAS G12C inhibitors in KRAS G12C cancer cells.
“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 [51]
The passage on inducible expression (section labeled Abstract; page unavailable) reports that expressing KRAS(G12V) in H358 cells attenuated the antiproliferative effects of sotorasib and adagrasib. The paper also identifies KRAS(G13D), but the cited passage does not show that its expression was tested for sufficiency. Thus, the evidence supports the claim for one identified KRAS mutant, not the plural claim as written. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Therapeutic pressure from KRAS inhibition can rapidly reshape tumor clonal architecture.
“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 [36]
The Abstract reports multiple subclonal alterations emerging during KRAS(G12C) inhibitor treatment. Its account of sequential cell populations describes clonal expansion and changing variant frequencies under drug selection. These findings support a change in clonal architecture, but the cited passages do not establish that it happens rapidly. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCombination strategies targeting KRAS G12C and upstream regulators or downstream effectors of RAS signaling have been extensively explored to overcome resistance to sotorasib or adagrasib.
“Combination strategies targeting KRAS G12C and upstream regulators or downstream effectors of the RAS signaling have been extensively explored to overcome resistance to sotorasib or adagrasib (9–12, 56).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [9]
The paper reports preclinical combinations of KRAS(G12C) inhibitors with downstream RAF, MEK, or ERK inhibitors in resistant models (Extended Data Figure 9; page not provided). It does not establish that combinations targeting upstream regulators were extensively explored, and it limits the potential benefit of the tested combinations to resistance involving emergent RAS or BRAF mutations. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCells containing mutations conferring KRASi resistance are frequently clonally or subclonally selected and can come to dominate much of the tumor post-relapse.
“Cells containing mutations conferring KRASi resistance are frequently clonally or subclonally selected and can come to dominate much of the tumor post-relapse [62,68,97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The paper reports treatment-emergent subclonal alterations in patients and a sweeping expansion of an NRAS-mutant clone in a drug-resistant cell-line lineage (Abstract; no page listed). But it does not establish that resistance-mutant cells frequently come to dominate much of a patient's tumor after relapse; most patient variants had low allele frequencies, and the authors call for tissue-based studies of progressive disease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome treatment-emergent KRAS secondary mutations not commonly observed in primary tumors, such as KRAS V8L and KRAS V14I, arise in patients who are relatively responsive to sotorasib (RECIST scores ≤ 30).
“Interestingly, some of the treatment-emergent KRAS secondary mutations that are not commonly observed in primary tumors, such as KRAS V8L and KRAS V14I, arise in patients who are relatively responsive to sotorasib (as defined by RECIST scores ≤ 30) [97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The paper’s main text (indexed as Abstract; page unavailable) identifies KRAS V8L among treatment-emergent secondary mutations, and reports that secondary RAS variants were uncommon in untreated KRAS(G12C) tumors. Our copy does not identify KRAS V14I as treatment-emergent or link either variant to patients with RECIST scores ≤30. It defines exceptional response by a complete or long-term partial response, not that RECIST cutoff. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn patient tumors with KRAS G12C analyzed post-sotorasib treatment, 14% displayed an additional or alternative point mutation in KRAS.
“In patient tumors with KRAS G12C that were analyzed post-sotorasib treatment, 14% of tumors displayed an additional or alternative point mutation in KRAS [97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The paper reports additional KRAS mutations after sotorasib treatment, but in 4 of 43 patients (about 9%), not 14%. It separately reports that the KRAS(G12C) allele was undetectable in 6 patients; that is not an additional or alternative point mutation. These findings appear in the passage discussing treatment-emergent alterations (page unavailable). (LLM, conf=0.89)
Experimental — accuracy not yet measuredPoint mutations in KRAS that confer resistance include G12D/F/R/V/W, V8L, G13D, V14I, Q61H, H95D/Q/R, Y96C, and Y96D.
“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 [97]
The paper reports treatment-emergent KRAS G12D, G12V, G12F, and V8L mutations in patients, and associates KRAS G13D with resistance in a preclinical model (Abstract; page unavailable). Our copy does not substantiate the remaining listed variants—G12R/W, V14I, Q61H, H95D/Q/R, or Y96C/D—or the stated mechanism that the G12 substitutions prevent covalent interactions with mutant cysteine. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMany novel mutations were observed at low subclonal frequencies, contributing to tumor heterogeneity.
“Many of the novel mutations were observed at low subclonal frequencies, contributing to tumor heterogeneity [97,103].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The Abstract reports that most treatment-emergent variants had low allele frequencies and suggests that multiple subclonal alterations underlie a heterogeneous pattern of resistance. It does not establish that all those low-frequency variants were subclonal or that they caused tumor heterogeneity: the authors caution that cfDNA sampling may also explain the low frequencies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCRISPR screens specifically investigating sotorasib resistance identified and validated ERK1/2, SHOC2, NRAS, CRAF, and BRAF as vulnerable targets synthetically lethal with KRAS inhibition.
“CRISPR screens specifically investigating sotorasib resistance identified and validated ERK1/2, SHOC2, NRAS, CRAF, and BRAF as vulnerable targets that were synthetically lethal with KRAS inhibition [97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The CRISPR-screen passage (page unavailable) reports that SHOC2, ERK2, NRAS, CRAF and BRAF guides were selectively depleted with sotorasib in resistant cells. It reports independent genetic validation for SHOC2 and NRAS, but not for every listed target; it also names ERK2, not ERK1/2, and describes selective vulnerabilities rather than establishing synthetic lethality for all five targets. (LLM, conf=0.89)
Experimental — accuracy not yet measuredDownstream effectors of KRAS signaling mutated post-KRAS inhibition included activating lesions in PIK3CA, MEK1, BRAF, and RAF1.
“The downstream effectors of KRAS signaling that were mutated post-KRAS inhibition included activating lesions in PIK3CA, MEK1, BRAF, and RAF1 [51,68,97,112].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The treatment-emergent alterations passage (Abstract section; page unavailable) reports BRAF mutations after sotorasib treatment. Our copy does not report post-treatment activating mutations in PIK3CA, MEK1, or RAF1; its mentions of MEK and CRAF concern other contexts, not such mutations. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTreatment-emergent mutations were observed in genes from other signaling pathways, including ALK, APC, CDKN2A/B, CTNNB1, IDH1/2, KEAP1, MET, MYC, NRAS, PTCH1, PTEN, RB1, RET, RICTOR, SMARCA4, and TP53.
“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 [97]
The paper’s main findings passage (indexed under Abstract; no page given) reports treatment-emergent NRAS mutations and IDH1/2 alterations, along with MET and MYC amplifications. It does not substantiate the full gene list in the claim; searches for ALK, APC, CDKN2A/B, CTNNB1, PTCH1, PTEN, RB1, RET, RICTOR, SMARCA4 and TP53 did not find passages identifying them as treatment-emergent. Calling the reported MET and MYC amplifications mutations is also imprecise. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMultiple mechanisms of acquired resistance to KRASG12C inhibitors have been identified, largely converging on reactivation of the RAS pathway or activation of parallel signaling pathways such as PI3K/mTOR.
“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 [14]
The Abstract reports multiple treatment-emergent alterations and shows that secondary RAS mutations can bypass KRAS(G12C) inhibition by reactivating ERK signaling. It describes resistance as heterogeneous and the RAS/BRAF mechanism as occurring in a subset; it does not establish that mechanisms largely converge on RAS reactivation or identify PI3K/mTOR activation as an alternative resistance pathway (pages not provided). (LLM, conf=0.85)
Experimental — accuracy not yet measuredMechanisms of acquired resistance in patients with lung and colorectal cancer treated with KRASG12C inhibitors include mutations in KRAS or other RTK-RAS-MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states.
“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 [19]
The patient-cohort passage (page unavailable) includes lung and colorectal cancer patients treated with sotorasib, and the treatment-emergent alterations passage reports KRAS, NRAS, BRAF, EGFR and FGFR2 alterations. The paper does not report histologic transformation to drug-resistant cell states; its discussion mentions adaptive resistance mechanisms but says that possibility was not experimentally tested in this study. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAcquired resistance to KRASG12C inhibition may be mediated by activation of multiple RTK regulators, including EGFR, FGFR, IGF1R, HER2, SHP2, and downstream RAS effectors such as MYC and mTOR.
“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 [8]
The treatment-emergent alterations passage (section labeled Abstract; page unavailable) reports EGFR, FGFR2 and MYC alterations in patients after KRAS(G12C) inhibition. Its preclinical findings instead associate acquired resistance chiefly with secondary RAS or BRAF mutations. The cited passages do not establish IGF1R, HER2, SHP2 or mTOR activation as resistance mechanisms. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVertical reactivation of RAS pathway elements has been observed in most samples from patients who developed resistance to KRASG12C inhibitors.
“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 [8]
The Abstract reports treatment-emergent RAS-pathway alterations and says secondary RAS mutations can reactivate ERK signaling. But it identifies secondary RAS mutations in 7 of 43 patients (16%) and describes the affected patients as a subset; it does not establish pathway reactivation in most patient samples. The 27 of 43 patients with treatment-emergent alterations also included changes in other genes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOne major route leading to recovery of RAS activity is activation of RTKs through genetic or non-genetic mechanisms.
“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 [8]
The results passage on treatment-emergent alterations (page unavailable in our copy) reports amplification and other alterations in the RTK genes EGFR, FGFR2 and MET after sotorasib treatment. It does not establish RTK activation as a major route to recovered RAS activity, or document RTK fusions or non-genetic RTK activation; its mechanistic results instead focus on secondary RAS and BRAF mutations. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA genome-wide CRISPR screen revealed that ABCC1 mediates MRTX849 resistance.
“A genome-wide CRISPR screen revealed that the adenosine triphosphate binding cassette transporter ABCC1 mediates MRTX849 resistance.”
From SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition (2024) · cites this paper as [14]
The Methods (CRISPR-CAS9 functional genetic screen; page unavailable) describe a genome-wide screen, but it tested sotorasib, not MRTX849. The results passage (labelled Abstract in our copy; page unavailable) identifies ERK-signaling genes including SHOC2 and NRAS; it does not report ABCC1 as a resistance mediator. (LLM, conf=0.88)
Experimental — accuracy not yet measuredReanalysis of a published genome-wide CRISPR-Cas9 screen identified ABCC1 as a top-ranked gene whose disruption could reverse resistance to the G12Ci AMG510.
“This screen identified ABCC1 as a top-ranked gene whose disruption could reverse resistance to the G12Ci AMG510 (Fig. 2F).”
From SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition (2024) · cites this paper as [14]
The Methods (CRISPR-CAS9 functional genetic screen; page unavailable) describe a genome-wide screen comparing resistant R1 cells with parental H358 cells under sotorasib treatment. The reported screen hits include SHOC2 and other ERK-signaling genes, but our copy does not identify ABCC1 as a top-ranked hit or show that its disruption reverses resistance. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSecondary RAS mutations and other genetic alterations are one of the most common mechanisms of acquired resistance to KRAS inhibitors in patients.
“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 [51]
The paper’s Abstract (page not supplied) reports treatment-emergent genetic alterations in 27 of 43 patients receiving sotorasib, including secondary RAS mutations in 7 of 43. It supports these as acquired-resistance mechanisms, but does not establish that secondary RAS mutations are among the most common mechanisms across KRAS inhibitors or patients generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredClinical efficacy of KRAS G12C inhibitors remains limited by intrinsic and acquired resistance, adaptive pathway reactivation, and tumor heterogeneity.
“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 [36]
The paper reports a 30–40% response rate and approximately six-month median progression-free survival in lung cancer, along with heterogeneous treatment-emergent resistance and ERK signaling reactivation (Abstract; page unavailable). It notes baseline KRAS amplification in preclinical models with weaker responses, but does not establish intrinsic resistance as a cause of limited clinical efficacy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe 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.
“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 [19]
G12Ci treatments are facing challenges due to the emerging development of drug resistance.
“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 [14]
Analysis of matched pre- and post-treatment specimens from 43 sotorasib-treated patients revealed treatment-induced genetic alterations in 27 patients, including 4 with secondary KRAS mutations and 3 with copy-number gains of KRAS.
“Analysis of matched pre- and post-treatment specimens from 43 (36 NSCLC, 3 CRC, and 4 other) sotorasib-treated patients revealed treatment-induced genetic alterations in 27 patients, including 4 with secondary KRAS mutations (G12D, G12V, G12F, V8L) and 3 with copy-number gains of KRAS [51].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [51]
In a study of sotorasib-treated patients, 7% developed KRAS G12C amplifications.
“In a study of sotorasib-treated patients, 7% of patients in the study developed KRAS G12C amplifications [97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
Time courses of G12C-mutant cell lines treated with increasing doses of G12C inhibitors demonstrated that the population frequency of rare resistance mutations increased over time.
“Time courses of G12C-mutant cell lines treated with increasing doses of G12C inhibitors demonstrated that the population frequency of rare resistance mutations increased over time [97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The mechanisms underlying differential sensitivity to KRASG12C inhibition are less well understood.
“While previous studies have characterized acquired resistance to KRASG12C inhibition and identified causal mutations and non-genetic mechanisms including RTK activation and epithelial-to-mesenchymal transition11–14,35, the mechanisms underlying differential sensitivity to KRASG12C inhibition are less well understood.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [14]
PIK3CA mutations can confer acquired resistance to KRAS G12C inhibitor and KRAS G12C inhibitor-cetuximab combination therapy in patients with NSCLC and CRC.
“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 [34]
The paper reports treatment-emergent alterations after sotorasib in patients with NSCLC and CRC, but its account of resistance does not identify PIK3CA mutations as a cause. Searches for PIK3CA and cetuximab found no passage supporting resistance to either KRAS(G12C) inhibitor monotherapy or a cetuximab combination through PIK3CA mutations. (LLM, conf=0.76)
Experimental — accuracy not yet measuredsgRNAs against CAB39, DUSP4, and NRBP1 were enriched in sotorasib-resistant cells, suggesting that their loss confers a selective advantage during treatment.
“sgRNAs against CAB39, DUSP4, and NRBP1 were enriched in sotorasib-resistant cells, suggesting that their loss confers a selective advantage during treatment [97].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [97]
The paper’s CRISPR-screen discussion and Methods describe sotorasib-treated resistant cells, but the reported hits are depleted sgRNAs targeting other genes, not enriched sgRNAs targeting CAB39, DUSP4, or NRBP1. A search for those three genes found no passage in our copy establishing their enrichment or a selective advantage from their loss. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThere remains an ongoing need for improved clinical outcomes, especially since emerging data indicate multiple mechanisms of acquired resistance in patients treated with sotorasib or adagrasib, many involving RAS pathway reactivation.
“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.”
Disease progression occurs in many patients treated with KRASG12Ci, and resistance is recapitulated in preclinical studies.
“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 [11]
Transcriptomic analysis of relapsed SW837 tumors did not identify secondary KRAS mutations, increased KRAS expression, or genomic aberrations previously reported in tumors with acquired resistance to KRASG12Ci.
“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 [11]
NCI-H358R cells generated by long-term culture in high-dose adagrasib retained KRASG12C and did not acquire any mutations associated with resistance in patients.
“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 [11]
Many of the aforementioned mutations were detected only at low frequencies and only in approximately half of patients relapsing on KRASG12Ci.
“Many of the aforementioned mutations were detected only at low frequencies and only in approximately half of patients relapsing on KRASG12Ci (ref. 11).”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [11]
Activating mutations in MRAS (Q71R) have been reported at low allelic frequency in KRASG12Ci-resistant NSCLC cell lines.
“activating mutations in MRAS (Q71R) have been reported at low allelic frequency in KRASG12Ci-resistant NSCLC cell lines11.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [11]
Pan-KRAS drugs would have advantages over mutant-selective drugs in heterogeneous cancers with multiple KRAS alterations at baseline or acquired resistance due to secondary KRAS on-target alterations.
“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 <i>KRAS</i> Mutants (2022) · cites this paper as [66]
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“14, 18, 19).”
BackgroundInfluentialChemical remodeling of a cellular chaperone to target the active state of mutant KRAS
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- Authors
- Zhao, Y., Murciano-Goroff, Y. R., Xue, J. Y., Ang, A., Lucas, J., Mai, T. T., Da Cruz Paula, A. F., Saiki, A. Y., Mohn, D., Achanta, P., Sisk, A. E., Arora, K. S., Roy, R. S., Kim, D., Li, C., Lim, L. P., Li, M., Bahr, A., Loomis, B. R., de Stanchina, E., Reis-Filho, J. S., Weigelt, B., Berger, M., Riely, G., Arbour, K. C., Lipford, J. R., Li, B. T., & Lito, P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Amgen (United States) (US)
- Corresponding author
- Lito, Piro
- ORCID
- Venue
- Nature
- Published
- 2021-11-10
- Volume
- 599
- Issue
- 7886
- Pages
- 679-683
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8887821
- OpenAlex
- W3212888956
- Cited by
- 479
- References
- 31
- Citations by year
- 2026: 95 · 2025: 90 · 2024: 127 · 2023: 99 · 2022: 65 · 2021: 3
- FWCI
- 47.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000457, U54OD020355, UL1TR001873)
- National Cancer Institute (R01CA230267, K08CA191082, R01CA087486, F30CA232549, P50CA247749, P30CA008748, R01CA230745)
- National Institute of General Medical Sciences (T32GM007739)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12C inhibitors, sotorasib, acquired drug resistance, lung cancer, RAS mutations, BRAF mutation, ERK signaling, subclonal evolution, patient-derived xenografts, single-cell sequencing, KRAS G12V, NRAS Q61K, FGFR2, EGFR, c-Myc
- MeSH terms
- Acetonitriles, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Female, Humans, Membrane Proteins, Mutation, Neoplasms, Piperazines, Pyridines, Pyrimidines, Cohort Studies, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, GTP Phosphohydrolases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mice
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