An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants Journal Article
| Authors: | Zafra, M. P.; Parsons, M. J.; Kim, J.; Alonso-Curbelo, D.; Goswami, S.; Schatoff, E. M.; Han, T.; Katti, A.; Calvo Fernandez, M. T.; Wilkinson, J. E.; Piskounova, E.; Dow, L. E. |
| Article Title: | An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants |
| Abstract: | KRAS is the most frequently mutated oncogene in cancer, yet there is little under- standing of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRAS(G1)(2C)), pancreas (KRAS(G12R)), and colon (KRAS(G13D)) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRAS(G13D) mutants are sensitive to EGFR inhibition, whereas KRAS(G12C)-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. SIGNIFICANCE: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents. |
| Keywords: | chemotherapy; progression; proliferation; inhibitors; progenitors; k-ras oncogene; egf receptor; gene-function; cancer; pancreatic-cell plasticity |
| Journal Title: | Cancer Discovery |
| Volume: | 10 |
| Issue: | 11 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-11-01 |
| Start Page: | 1654 |
| End Page: | 1671 |
| Language: | English |
| ACCESSION: | WOS:000583736200022 |
| DOI: | 10.1158/2159-8290.Cd-20-0442 |
| PROVIDER: | wos |
| PMCID: | PMC7642097 |
| PUBMED: | 32792368 |
| Notes: | Article -- Source: Wos |
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