Targeted therapies based on the presence of oncogenic driver alterations have improved the survival of cancer patients, however, the heterogeneity of responses and the emergence of drug resistance remain a critical challenge. Co-occurring alterations in tumor suppressor pathways may impact response to therapy in oncogene-driven tumors. Our recent work established a direct causal link between Keap1 and differential response to targeted therapy in an EGFR-driven lung cancer mouse model reflecting treatment outcomes in the human disease. Dissecting the role of the KEAP1 pathway in EGFR-driven lung tumors can reveal therapeutic vulnerabilities and lead to the development of genotype-specific therapeutic strategies.

To study the role of KEAP1 in limiting sensitivity to tyrosine kinase inhibitors (TKIs), we analyzed the impact of Keap1inactivation on tumor growth and molecular and histological profile in vivo. We found an increased Nrf2-mediated transcriptional signaling driven by Keap1 inactivation in EGFR-mutant tumors that could explain the reduced sensitivity to TKIs. Importantly, we observed that NRF2 was localized in the nucleus in absence of KEAP1 pathway alterations in EGFR-mutant patient-derived xenografts supporting that dysregulation of this pathway may occur due to non-genomic changes.

Future experiments will focus on understanding which specific Nrf2-activated pathways are enriched during treatment and whether dysregulation of the KEAP1 pathway can be extended to a broader subset of EGFR-mutant tumors. We will match these findings with clinical data from our Lung Cancer Tissue Collection (LCTC) to identify specific vulnerabilities for this subset of tumors and inform potential therapeutic strategies to improve outcomes in a specific subgroup of patients with lung cancer.