Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are commonly used to treat patients with EGFR+ non-small cell lung cancer (NSCLC). Unfortunately, despite the initial response, the long-term efficacy of the five clinically approved TKIs (i.e., gefitinib, erlotinib, afatinib, dacomitinib, osimertinib) is limited by the onset of resistance. Several mechanisms of resistance have been described, including the appearance of new EGFR mutations (e.g., T790M, C797S), activation of bypass pathways (e.g., AXL, HER2, MET and IGF1R) and phenotypic alterations (e.g., epithelial to mesenchymal transition, EMT). Additionally, in vitro treatment using EGFR TKIs leads to the establishment of drug tolerant persisters (DTPs), a cell population that might be responsible for the onset of resistance. In order to prevent resistance, the data we present herein propose to simultaneously target EGFR and other survival receptors (e.g., HER2 or HER3) by combining TKIs and specific monoclonal antibodies.

Materials and methods: Cultures of NSCLC cell lines, patient-derived and cell line xenografts were employed to test the efficacy of the drug combinations. In parallel, to better understand resistance to EGFR-TKIs we established NSCLC dacomitinib resistant (DR) cell lines that were used in vivo and in vitro.

Results: DR cells showed upregulation of AXL and IGF1R, features shared with the persister cells. We also demonstrate that combining TKIs and monoclonal antibodies successfully prevented TKI acquired resistance, by downregulating receptor kinases previously implicated in resistance to TKIs (e.g., MET and AXL), as well as by blocking pathways essential for mitosis (e.g., FOXM1).

Conclusions: Combining kinase inhibitors and antibodies in first line settings effectively avoids TKI resistance in animal models of lung cancer and might represent a long-term solution for EGFR positive NSCLC patients.

Citation Format: Ilaria Marrocco, Yuya Haga, Yosef Yarden. First-line therapy based on kinase inhibitors and antibodies prevents resistance in EGFR-mutated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1097.