Abstract B032: Deciphering the mechanisms of environmentally mediated Alectinib resistance in ALK+NSCLC

Abstract

Abstract Non-small cell lung cancer (NSCLC) is a devastating disease with a subset containing targetable oncogenic mutations that strongly benefit from targeted therapies. 3-7% of NSCLC patients bear an amplification of the Anaplastic lymphoma kinase (ALK) and Echinoderm microtubule-associated protein like 4 (EML4) fusion gene. These tumors typically show strong durable responses to first line therapy, Alectinib, an ALK tyrosine kinase inhibitors (ALK-TKIs). However, there is a high degree of patient-to-patient variability in the level of response to this drug; with some patients being innately resistant or less sensitive. Moreover, weak initial sensitivity to therapy has been linked to poor long-term responses with early acquisition of resistance. Thus, to improve clinical outcomes, we need to understand the mechanisms that lead to this reduced sensitivity to ALK inhibition. While, historically, reduced sensitivity to ALK TKI was thought to reflect cell intrinsic mechanisms, a growing body of evidence points to the importance of tumor microenvironmentally (TME) mediated mechanisms. We fortuitously encountered an observation of strong environment-mediated desensitization to Alectinib. We found that combining Alectinib with a small molecule inhibitor, Jumonji histone demethylase inhibitor, JIB04 in vitro overcomes tolerance, preventing ALK+NSCLC cells from developing resistance to Alectinib. Surprisingly, our validation experiments in mouse models revealed the opposite effect, where, JIB04 desensitized tumors to ALK inhibition. The disparity in the in vitro versus the in vivo response indicates the contribution of the TME in the reduced Alectinib sensitivity observed in vivo. The resistance phenotype in Alectinib+JIB04 treated mice was strongly associated with extensive inflammation in the tumor proximal tissues, along with higher circulating levels of inflammatory markers, IL6, LIF and monocytes, suggesting that inflammation may play a role in mediating this resistance. This is consistent with the recent findings where the markers of systemic inflammation such as Neutrophil to Lymphocyte ratio (NLR) have been associated with poor prognosis in ALK+NSCLC. While the mechanistic understanding is not well characterized, our model may help us explore the mechanisms of this correlation. Thus, our objective is to understand the underlying microenvironmental mechanism of this resistance to Alectinib. We hypothesize that Alectinib+JIB04 associated inflammation reduces ALK+NSCLC’s sensitivity to Alectinib. We envision two possibilities, either inflammation may directly affect resistance to Alectinib or indirectly where inflammation enhances tumor cell plasticity that then leads to resistance. We posit that the underlying molecular mechanisms of Alectinib+JIB04 mediated resistance are likely to be relevant to a subset of patients with poor initial responses with weak sensitivity or innate resistance to Alectinib observed in the clinics and will improve our knowledge about microenvironmental regulation of resistance. Citation Format: Pragya Kumar, Virginia Turati, Andriy Marusyk. Deciphering the mechanisms of environmentally mediated Alectinib resistance in ALK+NSCLC [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B032.