Abstract LB016: Targeting ATM modulates oncogenic pathways and amplifies chemotherapy efficacy in small cell lung cancer
Authors: Debdatta Halder, Utsav Sen, Vrinda Jethalia, Subhamoy Chakraborty, Yosuke Dotsu, Andrew Elliot, Ari Vanderwalde, Deniz Demircioglu, Dan Hasson, Triparna Sen
Journal: Cancer Research (2025)

Abstract Introduction: Small cell lung cancer (SCLC) is among the most aggressive and lethal lung malignancies, accounting for approximately 14% of all lung cancer cases. Characterized by the loss of TP53 and RB1 in most cases, SCLC exhibits high genomic instability. ATM kinase, a critical DNA damage repair (DDR) protein of the PIKK family, is highly expressed in cancers. High ATM expression correlates with resistance to ATR and PARP inhibitors, and ATM inhibitors improves therapeutic outcomes in DDR-deficient cancers. Despite this, the mechanistic underpinnings of ATM inhibition and its potential therapeutic applications in SCLC remain poorly understood. Methods: We employed a comprehensive approach that included the analysis of next generation sequencing (NGS) data, including RNA-sequencing from approximately 1,000 SCLC clinical samples, representing one of the largest and most comprehensive panels of cases to date. Additionally, we utilized an IC50 panel of two ATM inhibitors across a diverse panel of SCLC cell lines. Bulk RNA sequencing and mass spectrometry data were used to delineate the molecular effects of ATM inhibition. Functional assays, including western blot, qRT-PCR, cell cycle, and apoptosis analyses, were conducted to explore cell death pathways under ATM inhibition. Results: ATM expression was significantly elevated in SCLC clinical specimens, particularly in tumors with high YAP1 expression, as well as those with high co-expression of YAP1, ASCL1, NEUROD1, and/or POU2F3. Sensitivity to ATM inhibition was greater in SCLC cell lines than in non-small cell lung cancer (NSCLC), with vulnerability linked to the unfolded protein response and oxidative phosphorylation pathways. Transcriptomic and proteomic profiling revealed that ATM inhibition led to the downregulation of several oncogenic signaling pathways, including MYC and PI3K/AKT, and an upregulation of DNA damage response genes. ATM inhibition also increased intracellular oxidative stress, promoting cell death through apoptosis. Importantly, ATM inhibition synergized with standard chemotherapy agents, significantly enhancing therapeutic efficacy in preclinical models. Conclusions: Our findings highlight ATM as a critical therapeutic target in SCLC. ATM inhibition rewires the SCLC transcriptome and proteome, downregulating oncogenic pathways and enhancing the effectiveness of existing chemotherapy. This novel role of ATM provides a strong rationale for developing combination therapies targeting DDR and associated oncogenic pathways, paving the way for improved drug development and patient outcomes in SCLC. Citation Format: Debdatta Halder, Utsav Sen, Vrinda Jethalia, Subhamoy Chakraborty, Yosuke Dotsu, Andrew Elliot, Ari Vanderwalde, Deniz Demircioglu, Dan Hasson, Triparna Sen. Targeting ATM modulates oncogenic pathways and amplifies chemotherapy efficacy in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB016.