Mechanisms of Resistance to KRASG12C-Targeted Therapy
Open accessAbstract
KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRASG12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research. Significance: Although KRAS-targeted cancer therapy is revolutionary, tumors rapidly develop resistance. Understanding the mechanisms driving this resistance and designing combination strategies to overcome it are integral to achieving long-term disease control.
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Over 20% of KRAS-mutant NSCLC and PDAC cases have been found to have inactivating CDKN2A co-mutations.
“Over 20% of KRAS-mutant NSCLC and PDAC cases have been found to have inactivating CDKN2A co-mutations [122, 123].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [122]
The ‘Proliferative signaling as resistance mechanism’ section reports concurrent loss-of-function CDKN2A mutations in KRAS-mutant NSCLC, but says ‘up to 20%,’ not over 20%. It gives no corresponding CDKN2A prevalence for PDAC. (LLM, conf=0.91)
Experimental — accuracy not yet measuredA significant challenge with KRAS inhibitors is that the majority of patients do not respond, and initial responders will inevitably encounter disease progression.
“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 [11]
The Introduction reports response rates of approximately 30–40% for KRASG12C inhibitors, supporting the claim that most patients do not respond. The Proof of therapeutic targeting section says responses lasted only 4–6 months for most patients, but it does not establish that every initial responder will inevitably experience progression; the evidence is also specific to KRASG12C inhibitors. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSeveral resistance mechanisms to anti-KRASG12C inhibitors have been described, including bypassing signaling pathways, wild-type RAS signaling, increased proliferation via cell cycle disinhibition, and alteration of the immune response.
“Several resistance mechanisms to anti-KRASG12C have already been described [27]: (i) bypassing signaling pathways with reactivation of the KRAS-MAPK pathway via positive feedback from mediators upstream or downstream of the KRAS-MAPK cascade (Figure 2); (ii) signaling of the KRAS pathway mediated by wild-type forms of RAS (NRAS and HRAS) (Figure 2); (iii) increased proliferation via cell cycle dis”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [27]
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 [44]
The efficacy of RAS inhibitors remains low in colorectal cancer, with an overall response rate of only around 10%.
“the efficacy of RAS inhibitors remains low in colorectal cancer, with an overall response rate of only around 10% [44]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [44]
KRASG12C mutations are present in only 3-4% of colorectal cancer cases.
“KRASG12C mutations are present in only 3–4% of colorectal cancer cases”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [44]
Adagrasib showed a response rate of 42.9% in non-small cell lung cancer.
“Adagrasib also showed promising results with a response rate of 42.9% [44]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [44]
The response rate of KRASG12C inhibitors in colorectal cancer is approximately 10-20%.
“in colorectal cancer, it is around 10–20%”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [44]
Stimulation of ARS1620-treated cells with epidermal growth factor (EGF) resulted in reactivation of KRAS in the cells, strongly suggesting that EGFR mediates adaptive resistance to KRAS (G12C) inhibitors.
“Stimulation of ARS1620-treated cells with epidermal growth factor (EGF) resulted in reactivation of KRAS in the cells, strongly suggesting that EGFR mediates adaptive resistance to KRAS (G12C) inhibitors [97].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [97]
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 [97]
Induction of epithelial-to-mesenchymal transition (EMT) is associated with intrinsic and acquired resistance to KRAS (G12C) inhibition in cell lines previously sensitive to AMG510.
“Induction of epithelial-to-mesenchymal transition (EMT) is associated with intrinsic and acquired resistance to KRAS (G12C) inhibition in cell lines previously sensitive to AMG510.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [97]
Combining a KRAS (G12C) inhibitor with a PI3K or mTOR inhibitor could overcome the adaptive increase in PI3K signaling in mouse xenografts.
“Similarly, combining a KRAS (G12C) inhibitor with a PI3K or mTOR inhibitor could also overcome the adaptive increase in PI3K signaling in mouse xenografts [97, 114].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [97]
Drug resistance induced by EMT enhances PI3K/AKT signaling and MAPK signaling.
“Drug resistance induced by EMT enhances PI3K/AKT signaling and MAPK signaling [97, 127–129].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [97]
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References 47 · Cited by 156
- Authors
- Akhave, N. S., Biter, A. B., & Hong, D. S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Hong, David S.
- Venue
- Cancer Discovery
- Published
- 2021-04-05
- Volume
- 11
- Issue
- 6
- Pages
- 1345-1352
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8178176
- OpenAlex
- W3142714829
- Semantic Scholar
- 58518c05998f7c3c057bfb6b4208da3447851ab5
- Cited by
- 156
- References
- 47
- Citations by year
- 2026: 26 · 2025: 37 · 2024: 37 · 2023: 31 · 2022: 18 · 2021: 7
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C inhibitors, drug resistance, KRAS mutation, cell cycle transition, combination therapy
- MeSH terms
- Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Protein Kinase Inhibitors
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