Genetic determinants of egfr-driven lung cancer growth and therapeutic response in vivo

Giorgia Foggetti, Chuan Li, Hongchen Cai, Jessica A. Hellyer, Wen Yang Lin, Deborah Ayeni, Katherine Hastings, Jungmin Choi, Anna Wurtz, Laura Andrejka, Dylan G. Maghini, Nicholas Rashleigh, Stellar Levy, Robert Homer, Scott N. Gettinger, Maximilian Diehn, Heather A. Wakelee, Dmitri A. Petrov, Monte M. Winslow, Katerina Politi

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1736-1753
Number of pages18
JournalCancer Discovery
Volume11
Issue number7
DOIs
Publication statusPublished - 2021 Jul

ASJC Scopus subject areas

  • Oncology

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