EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases

Abstract

Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells, mouse models and human clinical specimens before onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to co-target EGFR to reduce risks of developing drug resistance.

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

“…7A, B; data not shown). While our manuscript was in submission a study, consistent with our findings, showed that RET and EGFR inhibitor combinations worked well against some RET-fusions (Vaishnavi et al, 2017). …”

Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

“…16–19,46 In addition, up-regulation of bypass signaling pathways (e.g., EGFR, RAS, and KIT) have also been reported. 20–22,47 …”

Recent Advances in Targeting ROS1 in Lung Cancer

“…However, the knowledge of bypass resistance mechanisms outlined above suggests potential therapeutic avenues one could pursue. For instance, an approach of co-targeting ROS1 and EGFR could be explored given the preclinical evidence for the role of EGFR in driving acquired resistance as well as adaptive survival response to ROS1-targeted therapy (70, 71). Additionally, an entrectinib-based regimen may soon enter early-phase clinical testing, combining the blockade of ALK/ROS1 and MEK, a critical downstream survival and proliferation pathway (71, 102).…”

“…Upregulation of EGFR signaling—not mediated by activating EGFR mutations at the DNA level—has been reported as a bypass mechanism in HCC78 cells made resistant to crizotinib (63, 69), although not yet validated in the clinic. Interestingly, in ROS1 -rearranged and other fusion kinase-driven cell line models, EGFR activation and signaling appears to serve as an important early adaptive survival response to TKI exposure (70). Another preclinical study has suggested a KRAS G12C mutation as a potential crizotinib resistance mechanism in ROS1 -rearranged lung cancer (71).…”