Abstract 1094: Genetic determinants of EGFR-driven lung cancer growth and therapeutic response in vivo
Authors: Foggetti Giorgia , Li Chuan , Cai Hongchen , Lin Wen-Yang , Ayeni Deborah , Hastings Katherine , Andrejka Laura , Maghini Dylan , Homer Robert , Petrov Dmitri A. , Winslow Monte M. , Politi Katerina 
Published: September 2020

Abstract
Oncogenic alterations in the Epidermal Growth Factor Receptor (EGFR) gene are found in ~15% of lung adenocarcinomas (LUADs). EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and these drugs are approved for the first-line treatment of patients with EGFR mutant lung cancer. Response rates to TKIs are high, however, there is variability in the duration and depth of response between patients and acquired resistance to TKIs inevitably emerges. EGFR mutant tumors harbor numerous additional co-occurring alterations in addition to the driver mutations that are likely to contribute to the malignant phenotype of these tumors and the variability in therapeutic response. TP53 is the most common tumor suppressor gene (TSG) co-mutated with EGFR, and alterations in TP53 correlate with worse outcomes upon TKI treatment. However, the functional contribution of loss of other LUAD-associated TSGs to tumor progression and drug resistance in EGFR mutant tumors remains poorly understood. To study the role of 10 putative tumor suppressor genes–that are frequently altered in human LUADs–for EGFR mutant tumors, we developed a conditional lung cancer model based on the inducible expression of EGFRL858R and deletion of Tp53 in the lungs via lentiviral delivery of Cre recombinase. We coupled this EGFRL858R;p53flox/flox mouse model with multiplexed CRISPR-Cas9-mediated genome editing and performed an in vivo screen to quantify the effects of inactivation of these 10 TSGs on tumor growth and TKI sensitivity. We found that inactivation of Apc, Rb1, and Rbm10 each strongly promoted growth while loss of Lkb1 or Setd2 reduced tumor growth. In contrast, in a KrasG12D;p53flox/flox model inactivation of Lkb1 or Setd2 were the strongest drivers of tumor growth. To establish the relevance of the functional data from mouse models for human tumors, we examined the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Consistent with the mouse data, of the 10 TSGs screened, APC, RB1 and RBM10 were the most frequently mutated in EGFR/TP53 mutant LUADs. We also tested whether inactivation of any of the 10 TSGs was associated with a reduced response to TKIs, by treating mice infected with the lentiviral pool targeting the TSGs with the 3rd generation TKI osimertinib and found that loss of Keap1 was associated with a diminished response to therapy. Collectively, our data have: i) uncovered striking specificity of TSG function in EGFR mutant LUADs, ii) discovered that inactivation of some TSGs can have diametrically opposite effects depending on the nature of the initiating oncogene and iii) established a causal link between certain tumor genotypes and differential responses to EGFR inhibition. Ongoing studies are aimed at investigating the mechanistic underpinnings of these findings.
Citation Format: Giorgia Foggetti, Chuan Li, Hongchen Cai, Wen-Yang Lin, Deborah Ayeni, Katherine Hastings, Laura Andrejka, Dylan Maghini, Robert Homer, Dmitri A. Petrov, Monte M. Winslow, Katerina Politi. Genetic determinants of EGFR-driven lung cancer growth and therapeutic response in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1094.