Resistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer

Abstract

The targeting of oncogenic ‘driver’ kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.

Molecular Changes Associated with Acquired Resistance to Crizotinib in ROS1-Rearranged Non–Small Cell Lung Cancer

“…An EMT-like feature, the loss of E-cadherin, was also observed in crizotinib-resistant tumors (patient 2) that did not harbor any ROS1 or alternative pathway mutation as determined by Nextera WES. Although TAE684-resistant HCC78 cells did not reveal EMT (14), crizotinib-resistant, ALK-rearranged H3122 cells showed an EMT-like, fibroblastic morphology similar to the HCC78CR1-2 cells in our study (20). This discrepancy might be due to the dual inhibition of ALK or ROS1 and c-MET.…”

“…These findings suggest that combined EGFR and ROS1 blockade might be a feasible strategy to overcome crizotinib resistance mediated by EGFR activation in ROS1-rearranged NSCLC. However, due to lack of EGFR upregulation in resistant tumors of patient 2, EGFR pathway activation might partly contribute to resistance to ROS1 inhibition, as observed in a previous study (14).…”

“…Despite the promising efficacy of crizotinib, ROS1-rearranged tumors developed acquired resistance to crizotinib after median progression-free survival of 19.2 months. The mechanism of acquired resistance to crizotinib was partly mediated by the ROS1 G2032R mutation in a patient with metastatic adenocarcinoma harboring CD74-ROS1 fusion (13) or EGFR pathway activation in a patient with NSCLC harboring SDC4-ROS1 fusion (14). However, due to the rarity of ROS1-rearranged NSCLC with acquired resistance to crizotinib, its mechanisms are not fully understood in ROS1-rearranged NSCLC.…”

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

“…Other mechanisms of resistance might include gain of function mutations of KIT (81), activation of the RAS pathway due to either KRAS/NRAS mutations or to KRAS amplification (82), rat sarcoma viral oncogene homolog, EGFR activation (83), and epithelial-to-mesenchymal transition (78,84).…”

Targeted Therapy of Lung Cancer With the Ros1 Rearrangement

“…Описано 2 основных механизма приобретенной резистентности -вторичные мутации в киназном домене ROS1, препят-ствующие связыванию препарата [20], и активация рецептора эпидермального фактора роста, что позволяет раковым клеткам обойти кризотиниб-опосредованное ингибирование ROS1-сигнала [21]. Некоторые препара-ты -ингибиторы ALK последующих поколений -могут быть эффективны при вторичных мутациях ROS1 [22,23].…”