IA31 Genetic Contributors to Tumor Progression and Drug Resistance in EGFR Mutant Lung Cancer

Abstract

Targeted therapies have transformed the landscape for the diagnosis and treatment of metastatic lung cancer. These tumors are now routinely tested for the presence of mutations or rearrangements in specific oncogenic drivers that, if present, predict sensitivity to targeted therapies directed to the genomic alterations present. Genotype-directed therapies have improved outcomes in specific subsets of patients with metastatic lung cancer. Despite this success, targeted therapies are not curative and acquired resistance is a major impediment to cures for patients treated with these therapies. Moreover, there is heterogeneity in the durability and depth of responses between patients. A paradigm for the success of targeted therapies in lung cancer comes from Epidermal Growth Factor Receptor (EGFR) mutant lung cancer. Mutations in exons encoding the tyrosine kinase domain of EGFR confer sensitivity to tyrosine kinase inhibitors (TKIs), and several are currently approved for the first-line treatment of EGFR mutant lung cancer. Most recently, the third-generation TKI osimertinib was approved and is increasingly being used in the first line. However, we have very limited knowledge of the mechanisms of resistance to osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal post-osimertinib treatment strategies remain to be defined. We modeled acquired resistance to first-line osimertinib treatment in transgenic mouse models of EGFRL858R-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR and identified therapeutic strategies to treat these tumors and prevent their emergence. Moreover, since EGFR mutant tumors in patients harbor additional genetic alterations beyond EGFR, many of them in tumor suppressor genes, we tested how the presence of co-occurring genetic alterations in tumor suppressor genes contributes to the progression and osimertinib sensitivity of the tumors in the mouse models of EGFR mutant lung cancer. Collectively, our findings highlight how genetically engineered mouse models of lung cancer, including those with complex genotypes, can be leveraged to study tumor progression and drug resistance in vivo.