WCLC 2025 - Posters & ePosters-EP.02.07 Enhancing Alectinib Efficacy in ALKPositive Non-Small Cell Lung Cancer by Targeting Mtor

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This study explores enhancing the efficacy of Alectinib, a key ALK inhibitor, in treating ALK-positive non-small cell lung cancer (NSCLC) by targeting the mTOR pathway. Despite Alectinib's success, up to 20% of patients experience disease progression within six months, underscoring the need for effective combination therapies.<br /><br />The research utilized a 3D cell culture model treated with Alectinib to perform high-throughput drug screening combined with multi-omics profiling (transcriptomics and proteomics) to pinpoint molecular mechanisms of sensitivity or resistance. From this screening, Everolimus, an mTOR inhibitor, was identified as a promising candidate to be paired with Alectinib.<br /><br />In vitro experiments across 19 ALK-positive NSCLC cell lines showed that combining Alectinib with Everolimus significantly enhanced cancer cell death over either drug alone. Dose-response analyses demonstrated synergy between the agents, as quantified by Combination Index (CI) values below 1, indicating more effective inhibition of cell viability. Imaging and viability assays further confirmed this synergistic induction of tumor cell apoptosis.<br /><br />In vivo xenograft mouse models treated with the Alectinib/Everolimus combination revealed improved therapeutic efficacy compared to monotherapies, supporting translational potential. This dual targeting approach addresses early resistance mechanisms seen with ALK inhibitor monotherapy.<br /><br />The study references prior work highlighting parallel signaling pathways that confer early resistance and rational polytherapy strategies targeting RAS-MAPK and mTOR pathways in ALK-positive lung cancer. These findings suggest that co-inhibition of ALK and mTOR may overcome limitations of current treatments.<br /><br />Supported by the University of Michigan Rogel Cancer Center and the Judith Tam ALK Lung Cancer Research Initiative, this research provides promising preclinical evidence for combining Alectinib with mTOR inhibition as a novel therapeutic strategy to improve outcomes in ALK-positive NSCLC patients at risk for early progression.

Asset Subtitle

Sofia D Merajver

Meta Tag

Speaker Sofia D Merajver

Topic Tumor Biology – Preclinical Biology

Keywords

Alectinib

ALK-positive non-small cell lung cancer

mTOR pathway

Everolimus

drug synergy

3D cell culture model

multi-omics profiling

combination therapy

xenograft mouse model

early resistance mechanisms