ArticleOncogene2018
Heterogeneity and mutation in KRAS and associated oncogenes: evaluating the potential for the evolution of resistance to targeting of KRAS G12C.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 42 citations in OpenAlex.
- Interleukin-1β as target to induce synthetic lethality in KRAS mutant biliary tract cancer.Clinical and molecular hepatology · 2026Article
- Driver mutation impact in Chinese hepatocellular carcinoma.PloS one · 2026Article
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- RASON promotes KRASJournal of experimental & clinical cancer research : CR · 2025Article
- Advances in the treatment of KRASCancer · 2025Review
- Article
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.eLife · 2024Article
- Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2024Article
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.bioRxiv : the preprint server for biology · 2024Article
- Unraveling the Drivers of Tumorigenesis in the Context of Evolution: Theoretical Models and Bioinformatics Tools.Journal of molecular evolution · 2023Review
- Drugging KRAS: current perspectives and state-of-art review.Journal of hematology & oncology · 2022Review
- The current state of the art and future trends in RAS-targeted cancer therapies.Nature reviews. Clinical oncology · 2022Review
- KRAS G12C-Mutant Non-Small-Cell Lung Adenocarcinoma: First Documented Report in the Arabian Gulf.Cureus · 2022Article
- Attribution of Cancer Origins to Endogenous, Exogenous, and Preventable Mutational Processes.Molecular biology and evolution · 2022Article
- Inhibition of colon cancer K-RasFrontiers in pharmacology · 2022Article
- Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit.Scientific reports · 2021Article
- KRAS G12C Mutations in NSCLC: From Target to Resistance.Cancers · 2021Review
- Getting quantitative on the effects of somatic mutation on cancer.Oncoscience · 2020Article
- KRAS G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples.Translational lung cancer research · 2020Article
- Targeting MutantBiomedicines · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Activating mutations in RAS genes are associated with approximately 20% of all human cancers. New targeted therapies show preclinical promise in inhibiting the KRAS G12C variant. However, concerns exist regarding the effectiveness of such therapies in vivo given the possibilities of existing intratumor heterogeneity or de novo mutation leading to treatment resistance. We performed deep sequencing of 27 KRAS G12-positive lung tumors to determine the prevalence of other oncogenic mutations within KRAS or within commonly mutated downstream genes that could confer resistance at the time of treatment. We also passaged patient-derived xenografts to assess the potential for novel KRAS mutation to arise during subsequent tumor evolution. Furthermore, we estimate the de novo mutation rate in KRAS position 12 and in genes downstream of KRAS. Finally, we present an approach for estimation of the selection intensity for these point mutations that explains their high prevalence in tumors. We find no evidence of heterogeneity that may compromise KRAS G12C targeted therapy within sequenced lung tumors or passaged xenografts. We find that mutations that confer resistance are even less likely to occur downstream of KRAS than to occur within KRAS. Our approach predicts that BRAF V600E would provide the highest fitness advantage for de novo-resistant subclones. Overall, our findings suggest that resistance to targeted therapy of KRAS G12C-positive tumors is unlikely to be present at the time of treatment and, among the de novo mutations likely to confer resistance, mutations in BRAF, a gene with targeted inhibitors presently available, result in subclones with the highest fitness advantage.
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Registered trials
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.