WCLC 2025 - Posters & ePosters-P3.03.32 Multi-Omic Characterization of ALK Fusion LUADs Reveals Overactivation of DNA Replication as a Contributor to ALK TKI Resistance

P3.03.32 Multi-Omic Characterization of ALK Fusion LUADs Reveals Overactivation of DNA Replication as a Contributor to ALK TKI Resistance

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This study analyzes the molecular mechanisms driving resistance to ALK tyrosine kinase inhibitors (TKIs) in ALK fusion-positive lung adenocarcinomas (LUADs). Although ALK rearrangements constitute around 5% of LUADs and are initially responsive to ALK-targeted therapies, resistance inevitably emerges, limiting long-term efficacy. Approximately 25% of resistance cases occur via non-genomic mechanisms, which are less understood.<br /><br />Comprehensive multi-omic profiling of clinical ALK-fusion LUAD samples revealed that about 50% of resistant tumors harbor ALK mutations combined with other genomic alterations, including MYC amplification. Transcriptomic analyses showed that DNA replication and cell cycle pathways are significantly upregulated in resistant tumors compared to TKI-sensitive ones. Additionally, patient-derived xenografts (PDXs) confirmed enrichment of pathways related to DNA replication, epithelial-to-mesenchymal transition, Hippo, and TGF-β signaling in resistant tumors, indicating complex and heterogeneous resistance mechanisms.<br /><br />Lorlatinib-resistant ALK-positive cell lines generated through prolonged drug exposure exhibited increased expression of DNA replication proteins and elevated DNA synthesis. Targeting DNA replication with carfilzomib, an FDA-approved proteasome inhibitor, synergized with lorlatinib, inducing cell cycle arrest and apoptosis in resistant cells. In vivo, the combination of lorlatinib and carfilzomib significantly delayed tumor growth in ALK-driven PDX models with acquired resistance.<br /><br />Genomic analysis identified frequent alterations beyond ALK mutations, including variants in TP53, CDKN2A/B, and MYC amplification, underscoring diverse resistance drivers. Pathway enrichment highlighted upregulated DNA replication, repair, and MYC targets, coupled with downregulated MAPK and histone deacetylation pathways in resistant tumors.<br /><br />In summary, this work elucidates the complex landscape of ALK TKI resistance, highlighting DNA replication overactivation as a key contributor. Therapeutically, combining lorlatinib with proteasome inhibition via carfilzomib offers a promising strategy to overcome acquired resistance in ALK-fusion LUADs, potentially improving patient outcomes.

Asset Subtitle

Esther Redin

Meta Tag

Speaker Esther Redin

Topic Tumor Biology – Translational Biology

Keywords

ALK fusion-positive lung adenocarcinoma

ALK tyrosine kinase inhibitors

drug resistance mechanisms

DNA replication pathways

MYC amplification

proteasome inhibitor carfilzomib

lorlatinib resistance

patient-derived xenografts

TP53 and CDKN2A/B alterations

combination therapy for ALK resistance