ArticleProceedings of the National Academy of Sciences of the United States of America2022
A saturation mutagenesis screen uncovers resistant and sensitizing secondary
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 27 citations in OpenAlex.
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- Magnesium as a conformational gatekeeper of KRAS: Structural dynamics and therapeutic implications.Protein science : a publication of the Protein Society · 2026Article
- Targeting TROP-2 in treatment-resistant non-small cell lung cancer harboring theOncology letters · 2026Article
- Massively parallel functional genomic assays in endocrinology: from promise to delivery.Journal of molecular endocrinology · 2026Review
- Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.Journal of medicinal chemistry · 2026Article
- Characterizing Variants of Uncertain Drug Resistance (VUDRs) Using Quantitative Measurements at Clinical Exposures.bioRxiv : the preprint server for biology · 2025Article
- Panobinostat potentiates adagrasib-induced cell death by triggering autophagy in human non-small cell lung cancer.Cell death discovery · 2025Article
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
- Orthogonal resistance mechanisms of classical- and induced-proximity inhibitors.bioRxiv : the preprint server for biology · 2025Article
- KRAS inhibitors: resistance drivers and combinatorial strategies.Trends in cancer · 2025Review
- Targeted therapy for KRAS G12C-mutated colorectal cancer: advances, challenges, and future directions.American journal of cancer research · 2025Review
- Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.bioRxiv : the preprint server for biology · 2024Article
- A pan-KRAS degrader for the treatment of KRAS-mutant cancers.Cell discovery · 2024Article
- Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel inTherapeutic advances in medical oncology · 2024Article
- Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation.JCI insight · 2023Article
- Article
- Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics.Molecular aspects of medicine · 2023Review
- Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors.Molecules (Basel, Switzerland) · 2023Review
- Direct GDP-KRASTherapeutic advances in medical oncology · 2023Review
- The current state of the art and future trends in RAS-targeted cancer therapies.Nature reviews. Clinical oncology · 2022Review
Corrections and comments
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Authors and funding
9 authors at 1 institution.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutant-specific inhibitors of KRASG12C, such as AMG510 (sotorasib) and MRTX849 (adagrasib), offer the unprecedented opportunity to inhibit KRAS, the most frequently mutated and heretofore undruggable oncoprotein. While clinical data are still limited, on-target mutations in KRASG12C at position 12 and other sites are emerging as major drivers of clinical relapse. We identified additional mutations in KRASG12C that impact inhibitor sensitivity through a saturation mutagenesis screen in the KRASG12C NCI-H358 non–small-cell lung cancer (NSCLC) cell line. We also identified individuals in population genetic databases harboring these resistance mutations in their germline and in tumors, including a subset that co-occur with KRASG12C, indicating that these mutations may preexist in patients treated with KRASG12C inhibitors. Notably, through structural modeling, we found that one such mutation (R68L) interferes with the critical protein–drug interface, conferring resistance to both inhibitors. Finally, we uncovered a mutant (S17E) that demonstrated a strong sensitizing phenotype to both inhibitors. Functional studies suggest that S17E sensitizes KRASG12C cells to KRASG12C inhibition by impacting signaling through PI3K/AKT/mTOR but not the MAPK signaling pathway. Our studies highlight the utility of unbiased mutation profiling to understand the functional consequences of all variants of a disease-causing genetic mutant and predict acquired resistant mutations in the targeted therapeutics.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.