Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

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. This article is highlighted in the In This Issue feature, p. 1601

Context Matters—Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer

“…One of the main reasons for multi-drug resistance is the genetic and molecular heterogeneity of cancer cells ( Gottesman et al, 2002 ). The impact of genetic alterations depends on oncogenic contexts and several studies showed that dysregulations should be analyzed in a tissue- or cancer entity specific manner ( Eser et al, 2013 ; Foggetti et al, 2021 ). Therefore, to identify much needed, effective treatment strategies for PDAC, its heterogeneity needs to be considered.…”

Retinoblastoma Protein Paralogs and Tumor Suppression

“…Mutation of these oncogenes also induce lung adenocarcinoma in mice (Fisher et al, 2001;Jackson et al, 2001;Ji et al, 2006;Politi et al, 2006). Foggetti et al used a CRISPR-Cas9 based approach to screen the effects of select mutations on development of lung adenocarcinoma initiated by Egfr/Trp53 or Kras/Trp53 mutations (Foggetti et al, 2021). Loss of Rb1, but not Cdkn2A, accelerated lung cancer progression induced by Egfr/Trp53 mutation.…”

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…More recently, NGS methods have developed from these specimens, notably for EGFR status evaluation at baseline [67]. NGS approaches are of strong interest in order to detect different genomic alterations associated in genes other than EGFR, which may explain, at least partially, some primary resistance of TKIs targeting EGFR mutations [68]. It will be certainly mandatory soon to evaluate the landscape of the different genomic alterations present in several genes and to assess other biomarkers in situ for a better prediction of therapeutic response to medications targeting EGFR mutations or to alternatively provide immunotherapy to these patients [68,69].…”

“…NGS approaches are of strong interest in order to detect different genomic alterations associated in genes other than EGFR, which may explain, at least partially, some primary resistance of TKIs targeting EGFR mutations [68]. It will be certainly mandatory soon to evaluate the landscape of the different genomic alterations present in several genes and to assess other biomarkers in situ for a better prediction of therapeutic response to medications targeting EGFR mutations or to alternatively provide immunotherapy to these patients [68,69]. It is noteworthy that these NGS methods will be applied not only in the late stages but also in the early stages of NS-NSCLC, which would mean patients receive adjuvant TKIs according to their EGFR status [70].…”