Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo
- Authors
- Foggetti, Giorgia; Li, Chuan; Cai, Hongchen; Hellyer, Jessica A.; Lin, Wen-Yang; Ayeni, Deborah; Hastings, Katherine; Choi, Jungmin; Wurtz, Anna; Andrejka, Laura; Maghini, Dylan G.; Rashleigh, Nicholas; Levy, Stellar; Homer, Robert; Gettinger, Scott N.; Diehn, Maximilian; Wakelee, Heather A.; Petrov, Dmitri A.; Winslow, Monte M.; Politi, Katerina
- Issue Date
- 7월-2021
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CANCER DISCOVERY, v.11, no.7, pp.1736 - 1753
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCER DISCOVERY
- Volume
- 11
- Number
- 7
- Start Page
- 1736
- End Page
- 1753
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/127740
- DOI
- 10.1158/2159-8290.CD-20-1385
- ISSN
- 2159-8274
- Abstract
- In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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