Abstract 6206: Combined inhibition of AXL and ATR enhances replication stress, cell death and immune response in small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor. Despite high initial responses to frontline chemo-immunotherapy, therapeutic resistance develops rapidly. There are limited treatment options in the relapsed setting, where the prognosis remains dismal. SCLC tumors experience continuous and high levels of replication stress (RS) due to ubiquitous loss of key cell cycle checkpoints, RB1 and TP53. Frequent amplification and high expression of the transcription factor cMYC further contribute to increased RS. Thus, high levels of RS expose a potential SCLC vulnerability and provide a therapeutic opportunity. Our group and others have shown that AXL, a TAM family receptor tyrosine kinase that is highly expressed in mesenchymal tumors, mediates resistance to chemotherapy, radiation and targeted therapies in SCLC, non-small cell lung cancer and other cancers, through its role in driving epithelial to mesenchymal transition (EMT). More recently, a novel role for AXL in DNA damage repair and tolerance has emerged. Therefore, we hypothesize that AXL targeting may be a potential therapeutic approach in SCLC. We first investigated the transcriptomic expression profile of AXL in SCLC clinical cohorts. AXL-high tumors were seen in a subset of treatment-naïve SCLC tumors, frequently among, but not limited to, the inflamed SCLC subtype. AXL expression was also seen in many relapsed SCLC tumors. As expected, tumors with high AXL expression also expressed several mesenchymal genes and higher EMT scores. Interestingly, among the treatment-naïve SCLC tumors, AXL expression was inversely correlated with a RS signature (rho=-0.54, p<0.001). Next, we tested the effects of AXL inhibition in SCLC in vitro and in vivo models. In a panel of 30 SCLC cell lines, bemcentinib, a selective AXL inhibitor in clinical trials for various advanced solid tumors, exhibited a range of antiproliferative activity, with IC50 values ranging from 41 nM to 10 µM (median IC50 3.1 µM). Bemcentinib also significantly delayed tumor growth in in vivo SCLC models. Biomarkers associated with sensitivity to bemcentinib in SCLC cell lines included markers of RS (cMYC, replication stress score) and DNA damage response (phospho CHK1S345, phospho CHK2T68). Bemcentinib also induced RS, indicated by the activation of ATR/CHK1-mediated RS response pathway, and DNA damage, and the combination with an ATR inhibitor (ceralasertib) showed a greater than additive effect. In a syngeneic model of SCLC, the combination of bemcentinib, ceralasertib and an anti-PDL1 antibody induced significant tumor regression. Together, these promising findings demonstrate that AXL inhibition may be an effective strategy to target the RS vulnerability common in SCLC. Citation Format: Kavya Ramkumar, C. Allison Stewart, Azusa Tanimoto, Qi Wang, Yuanxin Xi, Benjamin B. Morris, Runsheng Wang, Li Shen, Robert J. Cardnell, Jing Wang, Carl M. Gay, Lauren A. Byers. Combined inhibition of AXL and ATR enhances replication stress, cell death and immune response in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6206.