LAUSR

The successful treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which were already approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which is supposed to function as a pro-apoptotic protein that transduces TRAIL death signal to trigger apoptosis. Its expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL inhibition on DR4 expression and the underlying mechanisms. ALK-TKIs such as brigatinib and alectinib effectively and preferentially inhibited AKT/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true to DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather potently decreased DR4 mRNA expression. In parallel, they promoted degradation and decreased the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation on elucidating the biological significance of DR4 downregulation in ALK-targeted cancer therapy. Citation Format: Wen Zhao, Danlei Yu, Yifan Zhai, Shi-Yong Sun. ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. [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 4864.