Abstract B024: Clinical, genomic, and immune landscape of the receptor tyrosine kinase AXL in non-small cell lung cancer
Authors: Ramkumar Kavya , Corte Carminia M. Della , Diao Lixia , Cardnell Robert J. , Papadimitrakopoulou Vali A. , Heymach John V. , Wang Jing , Gibbons Don L. , Byers Lauren A. 
Published: March 2020

Therapeutic resistance limits effective treatment of non-small cell lung cancer (NSCLC) and a better understanding of mechanisms contributing to resistance and strategies to overcome these are urgently needed. AXL, a TAM family receptor tyrosine kinase, has emerged as a key determinant of resistance to chemotherapy, radiation and targeted therapies in NSCLC and other cancers, through its roles in mediating epithelial-mesenchymal transition (EMT) and immune escape. As several small-molecule AXL inhibitors and anti-AXL biologics are currently in clinical testing, AXL has emerged as a target of interest in treatment-resistant NSCLC. Here, we investigated AXL expression in NSCLC by analyzing genomic, transcriptomic and proteomic profiles across 3 treatment-naïve (1095 tumors) and 2 previously treated (245 tumors) clinical cohorts of lung adenocarcinoma and squamous cell carcinoma. While AXL expression did not vary with disease stage, tumor samples from patients with prior systemic treatment (and subsequent relapse) had significantly higher AXL expression and were more likely to have undergone EMT (based on our published EMT score), as compared to treatment-naïve NSCLC patients (p&lt;0.001). Although AXL-high tumors were seen in all histologic subtypes, AXL levels were 1.4-fold higher in lung adenocarcinoma than in squamous cell carcinoma (p&lt;0.001). Further analysis of driver genes in adenocarcinoma revealed that treatment-naïve NSCLC tumors with ALK translocations frequently had high expression of AXL at baseline (p=0.07), while approximately half of EGFR mutant NSCLC expressed high AXL mRNA. In contrast, tumors bearing mutations in STK11 and KEAP1 had relatively lower AXL expression (1.8-fold and 1.6-fold respectively, both p&lt;0.001). Similarly, the KRAS/STK11 co-mutation subgroup, which is associated with higher rates of inactivating KEAP1 mutations and an immune suppressed phenotype, had lower AXL levels as compared to the KRAS/TP53 or KRAS/CDKN2A/B co-mutation subgroups (p&lt;0.001). As AXL has been described to play a role in immune escape, we next investigated the association between AXL expression and immune response genes. AXL expression was strongly correlated with expression of immune suppressive mediators (TIM3, FOXP3, PD-L1 and PD-L2) as well as macrophage-recruiting factors (CCL2 and CSF-1). Furthermore, a significant correlation (rho &gt; 0.3; p&lt;0.001) between AXL expression and CXCL10 and CCL5, effector chemokines of STING-mediated innate immune response, was also observed in lung adenocarcinoma. In summary, our results show that AXL, which is associated with resistance to therapy, is present at higher levels in a significant subset of NSCLC tumors, including in treatment-naïve patients with ALK translocations and EGFR mutations. These findings suggest that early co-targeting of AXL along with standard therapies could improve therapeutic outcomes.

Citation Format: Kavya Ramkumar, Carminia M. Della Corte, Lixia Diao, Robert J. Cardnell, Vali A. Papadimitrakopoulou, John V. Heymach, Jing Wang, Don L. Gibbons, Lauren A. Byers. Clinical, genomic, and immune landscape of the receptor tyrosine kinase AXL in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B024. doi:10.1158/1535-7163.TARG-19-B024