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Inhibiting SCD expression by IGF1R during lorlatinib therapy sensitizes melanoma to ferroptosis
Furong Zeng1, Lin Ye2, Qian Zhou2
1Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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 to GPX4 inhibition in preclinical animal models, and melanoma patients with low GPX4 and IGF1R expression in their tumors survived for longer period. Altogether, lorlatinib sensitizes melanoma to ferroptosis by targeting IGF1R-mediated PI3K/AKT/mTOR signaling axis, suggesting that combination with lorlatinib could greatly expand the utility of GPX4 inhibition to melanoma patients with IGF1R-proficient expression.
Insights
Lorlatinib enhances melanoma cell death via ferroptosis by targeting IGF1R and the PI3K/AKT/mTOR pathway. This combination therapy shows promise for melanoma patients with specific biomarker expressions.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ferroptosis induction is a promising strategy for melanoma treatment.
- Enhancing sensitivity to ferroptosis is crucial for advancing melanoma therapy.
Purpose of the Study:
- To identify drugs that synergize with ferroptosis inducers for melanoma.
- To elucidate the molecular mechanisms underlying lorlatinib-mediated ferroptosis sensitization.
Main Methods:
- Drug synergy screen combining RSL3 (ferroptosis inducer) with 240 FDA-approved drugs.
- Inhibition of PI3K/AKT/mTOR signaling axis and SCD expression.
- Investigated lorlatinib's targets, including IGF1R, ALK, and ROS1.
- Preclinical animal models and analysis of melanoma patient tumor samples.
Main Results:
- Lorlatinib synergized with RSL3 to induce ferroptosis in melanoma cells.
- Lorlatinib sensitized melanoma to ferroptosis by inhibiting the PI3K/AKT/mTOR pathway and downstream SCD.
- IGF1R, not ALK or ROS1, mediated lorlatinib's effect on ferroptosis sensitivity.
- Combination therapy showed efficacy in preclinical models; low GPX4 and IGF1R expression correlated with better patient survival.
Conclusions:
- Lorlatinib sensitizes melanoma to ferroptosis through IGF1R-mediated inhibition of the PI3K/AKT/mTOR signaling axis.
- Combining lorlatinib with GPX4 inhibitors could benefit melanoma patients with IGF1R-proficient tumors.
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