KRAS G12C inhibition produces a driver-limited state revealing collateral dependencies
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Functional genomics reveals paths to enhancing combination therapies in KRAS-mutant cancers.
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CRISPRi experiments in other cancer cell types (AML, CML, pancreatic cancer and lung cancer cell lines) demonstrated that, unlike PSMA1, PTGES3 is not an essential gene upon knockdown.
“Furthermore, CRISPRi experiments in other cancer cell types (AML, CML, pancreatic cancer and lung cancer cell lines54–56) demonstrated that, unlike PSMA1, which is a positive control commonly essential gene, PTGES3 is not an essential gene upon knockdown (Extended Data Fig. 10d–g).”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [56]
The Results section ('Genome-scale CRISPRi screens nominate KRASG12C collateral dependent genes'; page unavailable) reports CRISPRi screens in pancreatic MIA PaCa-2 and lung H358 cancer cells. It does not report the claimed comparison of PTGES3 and PSMA1 essentiality, or experiments in AML or CML cells. (LLM, conf=0.78)
Experimental — accuracy not yet measuredCRISPRi screens using ARS-1620 in lung and pancreatic cancer cells identified SHP2 and CDK4 as collateral dependency genes whose targeting may potentiate KRASi in resistant cells.
“CRISPRi screens using the precursor G12C inhibitor ARS-1620 in lung and pancreatic cancer cells identified a broad range of genes both core (SHP2) and ancillary (CDK4) to RAS function as collateral dependency genes whose targeting may potentiate KRASi in resistant cells [113].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [113]
The Results sections on genome-scale CRISPRi screens and the CD map identify SHP2 and CDK4 as genes whose targeting can enhance response to ARS-1620 in lung and pancreatic cancer models. The Introduction proposes targeting collateral dependencies to address resistance, but the screened cell lines were described as highly sensitive to ARS-1620, not as resistant cells. Thus the resistant-cell qualifier remains a proposed application rather than a finding in those cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHER family and FGFR signaling are key mediators of adaptive feedback to RAS-MAPK pathway inhibitors.
“This finding is consistent with prior studies identifying HER family and FGFR signaling as key mediators of adaptive feedback to RAS-MAPK pathway inhibitors (10–14,21,22) and recent functional genomic screens(40).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [40]
CRISPRi-mediated suppression of HRAS, NRAS, TSC1/2, and NF1 led to resistance to KRASi.
“The CRISPRi-mediated suppression of HRAS, NRAS, TSC1/2, and NF1 led to resistance to KRASi [113].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [113]
The Results section describes CRISPRi screens measuring how gene knockdown affects susceptibility to the KRASG12C inhibitor ARS-1620, but it does not report resistance from suppressing the genes named in the claim. Searches for HRAS, NRAS, TSC1, TSC2, and NF1 found no passage establishing those gene-specific outcomes; the Methods list individually evaluated sgRNAs for other genes. No page numbers are available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn vitro and in vivo preclinical studies suggest additive and synergistic benefit of CDK4/6 and KRASG12C co-inhibition in models of NSCLC and PDAC.
“Moreover, in vitro and in vivo preclinical studies suggest additive and synergistic benefit of CDK4/6 and KRASG12C co-inhibition in models of NSCLC and PDAC149.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [149]
Adaptive response to G12C inhibitors can be minimized by combining G12C inhibitor with RTK or SHP2 inhibitors.
“These studies reported that adaptive response to G12C-Is could be minimized by combining G12C-I with RTK or SHP2-Is (Hallin et al., 2020; Lou et al., 2019; Ryan et al., 2020; Xue et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Lou et al., 2019
G12C inhibitors have significant but limited efficacy in KRAS-mutant malignancies, mostly due to adaptive resistance.
“G12C inhibitors (G12C-Is) have significant but limited efficacy in KRAS-mutant malignancies, mostly due to “adaptive resistance.””
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Lou et al., 2019
KRASG12C mutant cancer cell lines treated with G12C inhibitors develop adaptive resistance.
“Recent reports (and our unpublished observations; see Results) show that KRASG12C mutant cancer cell lines treated with G12C-Is also develop adaptive resistance (Hallin et al., 2020; Lou et al., 2019; Misale et al., 2019; Ryan et al., 2020; Xue et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Lou et al., 2019
Genetic and pharmacological screens identified RTK signaling to PI3K and mTOR, and autophagy, as collateral dependencies with KRAS and MAPK pathway inhibitors.
“These experiments have identified receptor tyrosine kinase (RTK) signaling to PI3K and mTOR (23, 37–40), as well as the autophagy pathway (30) as collateral dependencies with KRAS and MAPK pathway inhibitors.”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [39]
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“This finding is consistent with prior studies identifying HER family and FGFR signaling as key mediators of adaptive feedback to RAS–MAPK pathway inhibitors (10–14, 21, 22) and recent functional genomic screens (40).”
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How We Think about Targeting RNA with Small Molecules
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Inhibition of Nonfunctional Ras
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Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit
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Direct Modulators of K-Ras–Membrane Interactions
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Co-targeting KRAS G12C and EGFR reduces both mutant and wild-type RAS-GTP
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CRISPR and KRAS: a match yet to be made
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Direct GDP-KRAS G12C inhibitors and mechanisms of resistance: the tip of the iceberg
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Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments
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Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor
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Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer
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Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies
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KRAS inhibition in metastatic colorectal cancer: An update
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Conquering oncogenic KRAS and its bypass mechanisms
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KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination
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KRAS-G12C covalent inhibitors: A game changer in the scene of cancer therapies
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Can the Help Match the Hype? KRASG12C-Specific Inhibitors and Beyond
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Molecular Landscape and Therapeutic Strategies against Colorectal Cancer
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LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
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Self-citationKinase signalling adaptation supports dysfunctional mitochondria in disease
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- Authors
- Lou, K., Steri, V., Ge, A. Y., Hwang, Y. C., Yogodzinski, C. H., Shkedi, A. R., Choi, A. L. M., Mitchell, D. C., Swaney, D. L., Hann, B., Gordan, J. D., Shokat, K. M., & Gilbert, L. A.
- Affiliations
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shokat, Kevan M.
- Gilbert, Luke A.
- ORCID
- Venue
- Science Signaling
- Published
- 2019-05-28
- Volume
- 12
- Issue
- 583
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC6871662
- OpenAlex
- W2947368578
- Semantic Scholar
- 52229fb3a73a8f556950e50326eaac81d52db625
- Cited by
- 175
- References
- 58
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 23 · 2023: 23 · 2022: 32 · 2021: 38 · 2020: 25 · 2019: 4
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01CA190408, R00CA204602)
- Howard Hughes Medical Institute
- Samuel Waxman Cancer Research Foundation
- Stand Up To Cancer (SU2C-AACR-DT17-15)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, KRAS inhibitors, gene dependency, oncogene inhibition, target engagement, tumor cell survival
- MeSH terms
- Animals, Antineoplastic Agents, Cysteine, Female, Humans, Lung Neoplasms, Mice, Nude, Mutation, Neoplasm Transplantation, Oncogenes, Pancreatic Neoplasms, Protein Binding, Signal Transduction, Proto-Oncogene Proteins p21(ras), Sequence Analysis, RNA, Genomics, Proteomics, Cell Line, Tumor, Cell Proliferation, Mice, HEK293 Cells, CRISPR-Cas Systems
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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