Role of ERBB signaling in RET-rearranged lung cancer and contribution of EGFR amplification to cabozantinib resistance.

Abstract

11583 Background: Lung cancers driven by oncogenic RET fusions have lower response rates to targeted monotherapy such as cabozantinib (28%) relative to response rates typically observed in ALK- or ROS1- rearranged lung adenocarcinomas (60-80%). Methods: To identify targetable co-dependencies or cooperating pathways for RET fusion-positive lung cancers, we performed high-throughput chemical and genetic screens to find FDA-approved drugs or genes that when inhibited, would synergize with cabozantinib in RET fusion-positive lung cancer cell lines. In addition we performed NGS of a pair of pre-treatment and post-cabozantinib progression samples. Results: We identified EGFR siRNAs and anti-EGFR drugs as synergistic with cabozantinib. Combinations of drugs that target EGFR (cetuximab, afatinib, erlotinib, gefitinib, neratinib) and RET (cabozantinib, CEP-32496, lenvatinib, vandetanib) were more effective at reducing growth of RET cell lines than any single agent in vitro and in xenograft models. Cabozantinib treatment of RET fusion-positive cell lines inhibited EGFR and RET phosphorylation, an observation not seen in RET wild-type cell lines. Co-immunoprecipitation studies reveal that RET and EGFR interact. Ectopic expression of CCDC6-RET in NIH-3T3 or human bronchial epithelial cells resulted in upregulation of multiple ERBB receptors and ligands (not seen in a ROS1 fusion-positive cell line) and a concomitant increase in EGFR stability. Treatment with ERBB pathway ligands or overexpression of EGFR decreased sensitivity to cabozantinib in two RET fusion-positive cell lines. Finally, sequencing of a pair of pre-treatment and post-progression samples from a lung cancer patient treated with cabozantinib revealed acquired amplification of EGFR in the latter sample. Conclusions: Taken together, these results suggest that the tumorigenic potential of RET fusion oncogenes is dependent on deregulation of ERBB-activated pathways and that a combination of RET and EGFR drugs could be more effective in treating RET fusion-positive tumors. Moreover, amplification of EGFR is a potential driver of resistance to cabozantinib in RET-rearranged lung cancers.