Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Open accessAbstract
KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma 1,2. KRAS(G12C) inhibitors 3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation 4-6, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.
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The mechanisms of acquired resistance to adagrasib and sotorasib are currently unknown.
“The mechanisms of acquired resistance to these therapies are currently unknown.”
From Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [16]
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)
Experimental — accuracy not yet measuredDespite clinical benefit, acquired resistance to single-agent KRASG12C inhibitor therapy eventually occurred in most patients.
“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.”
From Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [16]
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)
Experimental — accuracy not yet measuredEach siRNA is processed by the endogenous RNA-induced silencing complex prior to binding to the target RNA, thereby inhibiting translation and promoting mRNA degradation.
“Each siRNA is then processed by the endogenous RNA-induced silencing complex prior to binding to the target RNA, in this case, KRAS, thereby inhibiting translation and promoting mRNA degradation [66,67,68].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [68]
The paper reports that KRAS-specific siRNAs inhibit new KRAS synthesis and that a KRAS(G12C)-specific siRNA suppresses signaling (Abstract; no page number provided). It does not describe processing by the RNA-induced silencing complex, binding to target RNA, or the proposed translation-inhibition and mRNA-degradation steps. (LLM, conf=0.84)
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 [68]
The Abstract (page unavailable) reports that some KRASG12C-mutant cells escape inhibition and resume proliferation while other cells are eliminated. It does not show that additional resistance-conferring mutations are clonally or subclonally selected, or that those cells dominate tumors after relapse. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSotorasib remains covalently bound to mutant KRAS, yet newly synthesized copies of mutant KRAS can still be activated by feedback, along with NRAS and HRAS, creating potential mechanisms of resistance to KRAS inhibitors.
“Sotorasib remains covalently bound to mutant KRAS, yet newly synthesized copies of mutant KRAS can still be activated by this feedback, along with its family members NRAS and HRAS, creating potential mechanisms of resistance to KRAS inhibitors [68,123].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [68]
The Abstract and Extended Data Fig. 10 describe newly synthesized KRAS(G12C) escaping inhibition when upstream signals maintain it in an active, drug-insensitive state. The paper discusses KRAS(G12C) inhibitors generally; these passages do not establish the claim specifically for sotorasib or report feedback activation of NRAS and HRAS. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Co-inhibition with AURKA inhibitor alisertib and G12C inhibitor ARS-1620 was highly synergistic in mouse models due to defective activation of RAF by KRAS G12C.
“Co-inhibition with AURKA inhibitor alisertib and G12C inhibitor ARS-1620 was highly synergistic in mouse models due to the defective activation of RAF by KRAS G12C [68].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [68]
The main text (page unavailable) reports synergistic antiproliferative effects in KRASG12C-mutant models and a stronger antitumor effect in mice, but does not establish that the mouse treatment was highly synergistic; the Methods specify that synergy was measured in cells. It attributes the enhanced inhibition of CRAF signaling to the combination disrupting KRASG12C interactions with AURK and CRAF, rather than to an inherent defect in RAF activation by KRASG12C. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAURKA is a KRAS G12C-CRAF interaction mediator that can bind directly to KRAS G12C and has been implicated in resistance to KRASi in CRISPR screens.
“AURKA is a KRAS G12C–CRAF interaction mediator that can bind directly to KRAS G12C and has also been implicated in resistance to KRASi in CRISPR screens [68].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [68]
The paper reports that AURKA interacts with KRAS G12C in cancer cells and suggests that the complex stabilizes KRAS G12C’s interaction with CRAF. It also reports that AURKA ranked highly in a genome-wide knockout screen for genes affecting response to a KRAS G12C inhibitor. However, the interaction was assessed by immunoprecipitation (Methods; Extended Data Fig. 8), which does not establish the claimed direct binding. (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 [11]
The paper’s Abstract (page unavailable) reports rapid adaptation to KRASG12C inhibition involving reactivation of KRAS-GTP and downstream signaling. It does not establish acquired resistance or identify PI3K/mTOR activation as an alternative mechanism; its discussion of PI3K concerns resistance to PI3K inhibitors, not KRASG12C inhibitors. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe 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 [11]
The citation is attached to the preceding claim about resistance mechanisms, not to the citing authors’ statement that differential sensitivity is less well understood. The paper’s Abstract describes rapid adaptation involving EGFR/RTK signaling, but the passages in our copy do not support attributing causal resistance mutations or epithelial-to-mesenchymal transition to this study. (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 [22]
The paper’s Abstract (page not supplied) reports rapid adaptive escape from KRASG12C inhibition in lung cancer cell models, involving EGFR and aurora kinase signaling. It does not establish acquired resistance in patients with lung and colorectal cancer, resistance-causing mutations in KRAS or other pathway effectors, or histologic transformation. (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 [21]
The Abstract reports adaptive reactivation of KRAS-GTP during inhibitor treatment in KRASG12C-mutant lung cancer cells and describes a mechanism by which some cells escape inhibition. It does not report findings from samples collected from patients with acquired resistance or establish that reactivation occurs in most such samples. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSome cells treated with KRAS G12C inhibitors exhibited elevated secretion of HBEGF, which promoted an adaptive response by activating EGFR and shifting oncogenic KRAS more toward the GTP-bound active state.
“For instance, some cells treated with KRAS G12C inhibitors exhibited elevated secretion of heparin-binding epidermal growth factor (HBEGF), which promoted an adaptive response by activating EGFR and shifting oncogenic KRAS more toward the GTP-bound active state [73].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [73]
The Abstract reports increased HBEGF secretion during KRAS G12C inhibitor treatment and evidence that EGFR signaling contributes to adaptive KRAS-GTP reactivation. It describes HBEGF secretion as a potential contributor that *could* activate EGFR, rather than demonstrating that secreted HBEGF itself caused the full EGFR-to-KRAS-GTP response asserted in the claim. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn KRAS G12C NSCLC cells developing acquired resistance to ARS-1620, AURKA was upregulated and directly bound to KRAS G12C to activate CRAF and promote adaptive reactivation of KRAS downstream signaling.
“In KRAS G12C NSCLC cells developing acquired resistance to ARS-1620, AURKA was found to be upregulated and directly bind to KRAS G12C to activate CRAF and promote adaptive reactivation of KRAS downstream signaling [73].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [73]
The paper reports that AURKA was upregulated in adapting cells, interacted with KRAS G12C, and enhanced reactivation of KRAS-GTP and CRAF/MEK/ERK signaling during inhibitor treatment (main text, labeled Abstract in our copy; Extended Data Fig. 8). Its Methods identify the inhibitor as ARS1620. The claim overstates the setting as acquired resistance: the paper describes rapid adaptation and escape from drug-induced quiescence, not established acquired resistance. It also describes an interaction and suggests stabilization of KRAS–CRAF binding, rather than demonstrating direct binding and CRAF activation as stated. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOther combinatorial partners including PI3K, mTOR, and Aurora Kinase inhibitors have been shown to have higher efficacy than EGFR inhibition in combination with KRAS G12C inhibition in lung cancer.
“other combinatorial partners including PI3K, mTOR, and Aurora Kinase inhibitors have been shown to have higher efficacy than EGFR inhibition in combination with KRAS G12C inhibition in lung cancer(10, 12, 13).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [13]
The main text (indexed under Abstract; page not supplied) reports that combining an Aurora kinase inhibitor with KRAS G12C inhibition had synergistic antiproliferative effects and a stronger antitumor effect than KRAS G12C inhibition alone. It also reports benefits from combining EGFR inhibition with KRAS G12C inhibition. It does not establish that the Aurora kinase combination is more effective than the EGFR combination, or report the claimed PI3K and mTOR combinations. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPLK1, AURKA, and PIK3CA have been reported as synthetic lethal genes that confer resistance to KRASG12C inhibition.
“PLK1, AURKA, and PIK3CA have been reported as synthetic lethal genes that confer resistance to KRASG12C inhibition [26, 27].”
From Feedback activation of EGFR/wild-type RAS signaling axis limits KRASG12D inhibitor efficacy in KRASG12D-mutated colorectal cancer (2023) · cites this paper as [26]
The paper’s main text (page unavailable) reports that AURKA expression attenuated the effect of KRASG12C inhibition, while AURKA knockout or inhibition prevented adaptive escape; combined inhibition had a synergistic antiproliferative effect. This supports AURKA’s role in resistance and a combination vulnerability, but the cited passages do not establish PLK1 or PIK3CA as synthetic-lethal genes in this setting, nor explicitly classify AURKA as one. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEGFR activation was found to be responsible for the adaptive response to ARS-1620 in NSCLC cells.
“EGFR activation was found to be responsible for the adaptive response to ARS-1620 in NSCLC cells [73].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [73]
RTK activation is responsible for elevated downstream signaling.
“Additionally, RTK activation is responsible for elevated downstream signaling [73, 76].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [73]
RTK activation upon KRAS G12C inhibition could be mediated by elevated ligand secretion.
“RTK activation upon KRAS G12C inhibition could be mediated by elevated ligand secretion.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [73]
Downstream 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 [68]
The paper’s Abstract describes rapid adaptation to KRAS(G12C) inhibition through new KRAS(G12C) production and EGFR/AURKA signaling, not acquired activating lesions in downstream effectors. Searches for PIK3CA, RAF1, and the claimed mutation list found no passage in our copy reporting post-inhibition mutations in PIK3CA, MEK1, BRAF, or RAF1. (LLM, conf=0.75)
Experimental — accuracy not yet measuredA nonuniform adaptive resistance process has been reported, where the equilibrium of resynthesized KRASG12C in ARS-1620-treated subpopulations was quickly shifted toward the ON state due to upstream RTK activation reducing target engagement of the OFF state inhibitor.
“A nonuniform adaptive resistance process has also been reported, where the equilibrium of resynthesized KRASG12C in ARS-1620–treated subpopulations was quickly shifted toward the ON state due to upstream RTK activation reducing target engagement of the OFF state inhibitor (44).”
Another major determinant of KRASG12C inhibitor resistance is the reactivation of upstream tyrosine kinase signaling that promotes SOS1-dependent GTP loading on RAS family members.
“Another major determinant of KRASG12C inhibitor resistance is the reactivation of upstream tyrosine kinase signaling that promotes SOS1-dependent GTP loading on RAS family members (19, 38, 44, 48–50).”
Therapeutic resistance to K-RasG12C inhibition is noted in preclinical tumor models and in the clinic.
“However, therapeutic resistance to K-RasG12C inhibition is not only noted in preclinical tumor models,10, 11, 12 but also in the clinic.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Adaptation of cells to K-RasG12C inhibition was dependent on new K-RasG12C synthesis, rather than activity of other wild-type Ras isoforms.
“In this study, the adaption of cells to K-RasG12C inhibition was dependent on new K-RasG12C synthesis, rather than the activity of other wild-type Ras isoforms.10”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Due to increased dependence on EGFR and SHP2 signal in surviving cells, newly synthesized K-RasG12C was maintained in its GTP-bound state to promote cell proliferation.
“Due to the increased dependence on epidermal growth factor receptor (EGFR) and SHP2 signal in surviving cells, newly synthesized K-RasG12C was maintained in its GTP-bound state to promote cell proliferation.10”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
The discrepancy between Xue et al. and Ryan et al. could not be solely attributed to diverse experimental systems because both used cell lines such as H358, H23, and H1792 and similar assays.
“This discrepancy could not be solely attributed to diverse experimental systems adopted between research groups since both of them used cell lines, such as H358, H23, and H1792 in ARS-1620 study, and GTP-bound K-Ras was further analyzed using similar assays.10,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Subpopulations of isogenic KRASG12C mutant cells responded to K-RasG12C inhibition in a heterogeneous manner.
“Recently, Xue et al.10 described an exquisite mechanism of the rapid adaption of cancer cells to K-RasG12C inhibitor and demonstrated that subpopulations of isogenic KRASG12C mutant cells responded to K-RasG12C inhibition in a heterogeneous manner.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
AURKA facilitates escape of initial drug-induced quiescence through interaction with K-RasG12C and downstream protein c-Raf.
“Furthermore, aurora kinase A (AURKA) was found to facilitate the escape of initial drug-induced quiescence through its interaction with K-RasG12C and downstream protein c-Raf.10”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
A subpopulation of cells rapidly generates acquired resistance to ARS-1620 by regaining K-Ras activity, while others become quiescent or undergo apoptosis.
“It is found that a subpopulation of cells rapidly generates acquired resistance to ARS-1620 by regaining K-Ras activity, while others would either be quiescent or undergo apoptosis.10”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Concurrent inhibition of SHP2 and K-RasG12C by small-molecule inhibitors such as SHP099 and ARS-1620 enhanced antiproliferative effects of KRASG12C inhibitors in both in vitro and in vivo models.
“Although how SHP2 activates Ras is still an open question, studies made by Ryan et al.,11 Xue et al.,10 and their colleagues showed that concurrent inhibition of SHP2 and K-RasG12C by small-molecule inhibitors (e.g., SHP099 and ARS-1620) enhanced the antiproliferative effects of KRASG12C inhibitors in both in vitro and in vivo models.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Co-targeting K-RasG12C with PI3K effectors such as AKT and mTOR is effective in preclinical studies.
“Furthermore, co-targeting K-RasG12C with PI3K effectors, such as ATK and mTOR has also been shown to be effective in a series of preclinical studies.6,7,10,15,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Because acquired resistance primarily occurs via adaptive RTK-SHP2-induced reactivation of Ras and downstream effectors, combining a K-RasG12C inhibitor with drugs targeting RTK signaling might be beneficial.
“Since acquired resistance primarily occurs via adaptive RTK-SHP2-induced reactivation of Ras and its downstream effectors,10,11 combining K-RasG12C inhibitor with drugs targeting RTK signaling might be beneficial.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Trajectory analysis of ARS-1620-treated cells revealed heterogeneous adaptations to K-RasG12C inhibition.
“In addition, trajectory analysis of ARS-1620-treated cells revealed heterogeneous adaptations to K-RasG12C inhibition.10”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Xue et al. discovered AURKA as a novel target by combining single-cell RNA sequencing with CRISPR-Cas9 screening.
“In another study, Xue et al.10 discovered a novel target, AURKA, by combining the results of single-cell RNA sequencing with CRISPR-Cas9 screening.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Significant synergy was observed between ARS-1620 and alisertib, a specific AURKA inhibitor, in treating ARS-1620-refractory KRASG12C mutant cancers.
“Significant synergy was observed between ARS-1620 and alisertib, a specific AURKA inhibitor in treating ARS-1620-refractory KRASG12C mutant cancers.10”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
Adaptive Ras reactivation through the RTK-SHP2 pathway is one of the well-characterized mechanisms accountable for acquired resistance to K-RasG12C inhibition.
“Adaptive Ras reactivation through RTK-SHP2 pathway is one of the well-characterized mechanisms accountable for acquired resistance to K-RasG12C inhibition.10,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [10]
In NSCLCs and CRCs, KRASG12C inhibition leads to accumulation of activated upstream EGFR and/or other ERBB family members, facilitating escape from KRASG12C-inhibitor monotherapy.
“In NSCLCs and CRCs, KRASG12C inhibition leads to an accumulation of activated upstream EGFR and/or other ERBB family members, which facilitates escape from KRASG12C-inhibitor monotherapy110,121–124.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [110]
Several studies have shown that RAS-MAPK pathway reactivation occurs upon KRASG12C-inhibitor treatment.
“several studies have shown that similar pathway reactivation occurs upon KRASG12C-inhibitor treatment50,110–113.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [110]
KRASG12C is not permanently GTP-bound and depends on upstream RTK signaling for GEF-mediated GTP reloading.
“KRASG12C is not permanently GTP-bound and maintains a dependency on upstream receptor tyrosine kinase (RTK) signaling for GEF-mediated GTP reloading (9, 10).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [10]
The rationale for SHP2 and SOS1 inhibitors as pan-KRAS inhibitors is that several KRAS oncoproteins, including G12C, cycle between inactive and active states and rely on upstream activation and nucleotide exchange for full transforming potential.
“The rationale for pursuing SHP2 and SOS1 inhibitors as pan-KRAS inhibitors is grounded in the evidence that several (K)RAS oncoproteins, including KRASG12C, still cycle between an inactive and active state and rely on upstream activation and nucleotide exchange to exhibit their full transforming potential (9–13, 33, 34).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [10]
KRASG12C active state inhibitors are expected to address adaptive changes of KRAS resulting in production of new, active KRAS.
“In addition, KRASG12C active state inhibitors are expected to address adaptive changes of KRAS resulting in the production of new, active KRAS (10).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [10]
The response rate of KRASG12C inhibitors in lung cancer is approximately 40%.
“the response rate in lung cancer is approximately 40%”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [43]
Sotorasib demonstrated high efficacy in non-small cell lung cancer, with a response rate of 33.3%, stable disease rate of 57.9%, and disease control rate of 91.2%.
“sotorasib demonstrated high efficacy in non-small cell lung cancer, with a response rate of 33.3%, stable disease rate of 57.9%, and disease control rate of 91.2% [43]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [43]
KRAS proteins primarily bind GDP and are in an inactive conformation maintained by intrinsic GTP hydrolytic activity.
“KRAS proteins primarily bind to guanosine diphosphate (GDP) and are in an inactive conformation maintained by intrinsic guanosine triphosphate (GTP) hydrolytic activity.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [7]
Since KRAS (G12C) inhibitors only bind to KRAS-GDP conformation, drug resistance may occur in cells with increasing GTP-bound KRAS.
“Since KRAS (G12C) inhibitors only bind to KRAS-GDP conformation, drug resistance may occur in cells with increasing GTP-bound KRAS [7].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [7]
Xue et al. found increased new KRAS (G12C) protein in KRAS (G12C)-mutant tumor cells and elucidated that EGFR can promote the conversion of KRAS from the GDP state to the GTP-bound state and AURKA can maintain its active state by binding to KRAS.
“Xue et al. found the increased new KRAS (G12C) protein in KRAS (G12C)-mutant tumor cells and elucidate that EGFR can promote the conversion of KRAS from the GDP state to the GTP-bound state (activated state) and AURKA can maintain its active state by binding to KRAS [7].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [7]
SHP2 inhibitors can restore the sensitivity of KRAS-mutant NSCLC to MEK inhibition and increase inactive GDP-bound KRAS.
“SHP2 inhibitors can restore the sensitivity of KRAS-mutant NSCLC to MEK inhibition and increase inactive GDP-bound KRAS.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [7]
Acquired or adaptive resistance to KRAS G12C inhibitors is a major concern and can limit the long-term therapeutic utility of these treatments.
“the fact that they are targeted therapies inevitably means they are vulnerable to the development of intrinsic or adaptive resistance;[ 6, 7 ] such resistance can severely limit the long‐term therapeutic utility of these treatments.”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [6]
Drug resistance to KRAS G12C inhibitors eventually develops with long-term treatment.
“Preclinical and clinical data have revealed that drug resistance to KRAS G12C inhibitors eventually develops with long‐term treatment.[ 6, 33, 41 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [6]
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Self-citationEGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer.
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“org have higher efficacy than EGFR inhibition in combination with KRASG12C inhibition in lung cancer (10, 12, 13).”
BackgroundSelf-citationDiverse alterations associated with resistance to KRAS(G12C) inhibition
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“…alterations at the time of acquired resistance were observed in several patients, including amplifications/gains of KRAS G12C (patients 6, 9, 13, 22), amplification/ gain of EGFR (patients 2, 13), activating PIK3CA mutations (patients 13, 22), and an oncogenic NFE2L2 D29H variant (patient 21; Fig.”
BackgroundSHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
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Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC
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Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer
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Current therapy of KRAS-mutant lung cancer
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Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
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The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS
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“PLK1, AURKA, and PIK3CA have been reported as synthetic lethal genes that confer resistance to KRAS inhibition [26, 27].”
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Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
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KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population
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Overcoming Resistance to Drugs Targeting KRAS Mutation
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KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
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“Combining the KRAS G12D inhibitor MRTX1133 with one or more immune checkpoint blockades was more effective than MRTX1133 as a single agent in a murine model of PDAC [132].”
BackgroundInfluentialPAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib
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Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
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Resistance looms for KRASG12C inhibitors
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Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer
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Self-citationSRC kinase drives multidrug resistance induced by KRAS-G12C inhibition
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The Next Generation of KRAS Targeting: Reasons for Excitement and Concern
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The Research Progress of Direct KRAS G12C Mutation Inhibitors
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Synergy of EGFR and AURKA Inhibitors in <i>KRAS</i> -mutated Non–small Cell Lung Cancers
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WEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer
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LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
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Self-citationExploiting the intrinsic misfolding propensity of the KRAS oncoprotein
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Hedgehog signalling is involved in acquired resistance to KRASG12C inhibitors in lung cancer cells
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“4,8,20,21 8, 22– 25 Our study similarly multiple RTKs in AMG510-R AMG510-R Previously, we demonstrated that SDC1 plays a critical role for oncogenic KRAS-mediated macropinocytosis, 12 a nutrient salvage process that supports oncogenic growth.”
Differential Response and Resistance to KRAS-Targeted Therapy
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“For instance, some cells treated with KRAS G12C inhibitors exhibited elevated secretion of heparin ‐ binding epidermal growth factor (HBEGF), which promoted an adaptive response by activating EGFR and shifting oncogenic KRAS more toward the GTP ‐ bound active state [75].”
InfluentialAdaptive Feedback Signaling Through the FAK/SRC Pathway Promotes KRAS G12C Inhibitor Resistance
Udagawa, H., Shibata, Y., Nilsson, M. B., Nishii, K., Robichaux, J. P., Galan-Cobo, A., He, J., Poteete, A., Qian, Y., Molkentine, D., et al. (2026) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2026.103991 · Cited by 1 · see citing works
- Authors
- Xue, J. Y., Zhao, Y., Aronowitz, J., Mai, T. T., Vides, A., Qeriqi, B., Kim, D., Li, C., de Stanchina, E., Mazutis, L., Risso, D., & Lito, P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Padua (IT)
- Corresponding author
- Lito, Piro
- Venue
- Nature
- Published
- 2020-01-08
- Volume
- 577
- Issue
- 7790
- Pages
- 421-425
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7308074
- OpenAlex
- W2999810289
- Cited by
- 543
- References
- 56
- Citations by year
- 2026: 66 · 2025: 86 · 2024: 87 · 2023: 87 · 2022: 80 · 2021: 92 · 2020: 44
- FWCI
- 24.82
- 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)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Institutes of Health (U54OD020355)
- National Cancer Institute (R01CA230267, K08CA191082, F30CA232549, P30CA008748, R01CA230745)
- National Institute of General Medical Sciences (T32GM007739)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- 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
- Keywords
- KRAS G12C, KRAS inhibitors, drug resistance, single-cell responses, quiescent cancer cells, mitogen-activated protein kinase, epidermal growth factor receptor, Aurora kinases, lung adenocarcinoma, tumor heterogeneity
- MeSH terms
- Adaptation, Biological, Enzyme Inhibitors, Humans, Lung Neoplasms, Mutation, Signal Transduction, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, ErbB Receptors
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