Abstract B012: Impact of stromal protection on in-vivo response to ALK targeted therapies in NSCLC
Authors: Desai Bina , Marusyk Viktoriya , Miroshnychenko Daria , Gatenbee Chandler , Rix Uwe , Anderson Alexander , Haura Eric , Marusyk Andriy 
Published: May 2022

Lung cancer accounts for most cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is most prominent histological subtype of lung cancer. About 5-7% of NSCLC shows constitutive activation of oncogenic anaplastic lymphoma kinase (ALK). Though clinical introduction of tyrosine kinases inhibitors (TKIs) for ALK, has improved patient survival, it did not translate into cures as acquired resistance inevitably emerges in patients with advanced and metastatic cancers. While some of the tumor cells are capable of surviving therapy due to their intrinsic characteristics, inability of therapies to eliminate all of the tumor cells also reflects a contribution by microenvironmental factors. As a major cellular component of tumor microenvironment, cancer associated fibroblasts (CAFs) have emerged as the key determinant of environmental protection. Many in-vitro studies have demonstrated that CAF-produced paracrine factors can dramatically blunt the effect of TKIs by providing alternative mitogenic and survival signals. While the ability of CAFs to protect tumor cells from TKI is well documented in-vitro, whether the impact of stromal protection is relevant in-vivo remains unresolved. To study the impact of CAF in response to ALK TKI, we isolated multiple derivatives of CAFs from patient’s tumor resections. Consistent with previously reported studies we observed that co-culture as well as conditioned media from CAFs protects tumor cells against ALK TKIs. This degree of protection in-vitro was highly correlated with the level of hepatocyte growth factor (HGF) measured from each CAF isolates. To study the impact of HGF-mediated protection to tumor cells in-vivo, we took advantage of inability of murine HGF to activate its unique receptor cMET in human cells. Specifically, we compared response of tumors to the frontline ALK TKI: alectinib between tumors growing in regular NSG xenografts and those grown in NSG derivate with humanized HGF. Contrary to our in-vitro based expectations, we observed only minor differences in tumor responses between the two strains. Using spatial histology analyses, we found that rather than irrelevance of HGF-cMET axis in-vivo, this lack of substantial differences reflected strong HGF independent stromal protection effect, which was maintained through different phases of tumor responses, including relapse. Surprisingly, this protection was partially retained in relapsing tumors, suggesting that stroma can contribute not only to persistence, but also to resistance. Our ongoing efforts are focused on determining what molecular mechanisms underlying stromal protection in-vivo, and on interplay between cell-intrinsic and stromal resistance. Addressing these questions will provide knowledge necessary to the development of more effective therapeutic strategies against ALK+ NSCLC.

Citation Format: Bina Desai, Viktoriya Marusyk, Daria Miroshnychenko, Chandler Gatenbee, Uwe Rix, Alexander Anderson, Eric Haura, Andriy Marusyk. Impact of stromal protection on in-vivo response to ALK targeted therapies in 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 B012.