Inhibiting SCD expression by IGF1R during lorlatinib therapy sensitizes melanoma to ferroptosis.

ABSTRACT: Induction of ferroptosis is an emerging strategy to suppress melanoma progression. Strategies to enhance the sensitivity to ferroptosis induction would be a major advance in melanoma therapy. Here, we used a drug synergy screen that combined a ferroptosis inducer, RSL3, with 240 anti-tumor drugs from the FDA-approved drug library and identified lorlatinib to synergize with RSL3 in melanoma cells. We further demonstrated that lorlatinib sensitized melanoma to ferroptosis through inhibiting PI3K/AKT/mTOR signaling axis and its downstream SCD expression. Moreover, we found that lorlatinib's target IGF1R, but not ALK or ROS1, was the major mediator of lorlatinib-mediated sensitivity to ferroptosis through targeting PI3K/AKT/mTOR signaling axis. Finally, lorlatinib treatment sensitized melanoma

SUBMITTER: Zeng F 

PROVIDER: S-EPMC10009726 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature