Cellworks Study Identifies Genomic Markers of Chemotherapy Benefit and Resistance in Advanced NSCLC

Patients with TP53, KRAS, and CD274 aberrations showed decreased chemotherapy benefit, while ATM and ATR variants were linked to increased chemo-immunotherapy sensitivity

National Harbor, MD, November 10, 2025 – Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Best-in-Class PTRS, today announced new findings identifying key genomic markers that influence patient response to chemo-immunotherapy (ICI+C) in advanced non-small cell lung cancer (NSCLC). These discoveries demonstrate the predictive capability of the Cellworks Platform to advance a personalized approach to NSCLC treatment selection that maximizes benefit, while minimizing unnecessary toxicity.

Results from the study were featured in a poster presentation, “Identification of Genomic Aberrations Contributing to the Prediction of Chemotherapy Benefit in Advanced NSCLC,” during the Society for Immunotherapy of Cancer (SITC) 2025 Annual Meeting, held November 7-9 at the Gaylord National Resort & Convention Center, in National Harbor, Maryland.

“Identifying specific mutations that underlie chemotherapy resistance represents a significant step forward in advancing personalized treatment for patients with NSCLC,” said Charu Aggarwal, MD, MPH, FASCO, the Leslye M. Heisler Professor of Lung Cancer Excellence in the Perelman School of Medicine at the University of Pennsylvania, and lead author of the study. “This study deepens our understanding of how DNA damage response and immune signaling pathways interact in determining chemo-immunotherapy outcomes. By pinpointing genomic features that impact response, we can better tailor therapy selection, avoid unnecessary toxicity, and improve outcomes for patients with advanced disease.”

Study Highlights and Key Findings

While ICI+C therapy is a standard treatment for advanced NSCLC, patient outcomes vary widely. This study builds on the breakthrough myCare-040 study presented at WCLC 2025, which validated the predictive capability of the Cellworks Platform and ∆TRI algorithm to identify patients most likely to benefit from ICI+C therapy versus immunotherapy alone. The new biosimulation analysis extends those findings by identifying specific genomic aberrations that drive therapeutic benefit or resistance to chemotherapy. Notably, these aberrations were observed across both benefit groups, limiting their utility as single biomarkers.

• Chemotherapy-Related Associations - Twenty-four of the 592 genomic aberrations (4.1%) identified in the myCare-040 cohort were significantly associated (p < 0.05) with either benefit or non-benefit from ICI+C therapy.

• Chemotherapy Resistance Markers - Mutations in TP53, KRAS, and CD274 amplification occurred more often in patients who did not benefit from ICI+C (TP53-SOF, p < 0.0001, FDR < 0.0001; KRAS-SOF, p = 0.007; CD274 amplification, p = 0.006).

• Chemotherapy Sensitivity Drivers - ATM-LOF and ATR-LOF mutations, both DNA damage response genes, were most prevalent in patients within the ICI+C benefit group (ATM-LOF, p < 0.0001, FDR < 0.0001; ATR-LOF, p = 0.003).

“Traditional biomarkers such as PD-L1 or TMB only reveal part of the picture,” said James Wingrove, PhD, Chief Development Officer at Cellworks. “Mechanistic biosimulation allows us to capture the dynamic interplay between DNA damage response, chemotherapy sensitivity, and immune activation—providing a scientifically grounded foundation for individualized treatment decisions.”

“The ability to connect molecular biology with real-world therapeutic outcomes represents a major advance in personalized therapy selection,” said Michael Castro, MD, Chief Medical Officer at Cellworks. “By integrating DNA repair, oncogenic signaling, and immune modulation pathways, this study provides a more complete mechanistic framework for understanding chemo-immunotherapy outcomes than single-gene biomarkers can offer.”

The Cellworks Platform

The Cellworks Platform performs computational biosimulation of protein-protein interactions, enabling in silico modeling of tumor behavior using genomic data from next-generation sequencing (NGS). This approach allows clinicians to evaluate how personalized treatment strategies interact with a patient’s unique tumor network. At the core of the platform is the Cellworks Computational Biology Model (CBM), a mechanistic network encompassing more than 6,000 human genes, 30,000 molecular species, and 600,000 molecular interactions. The CBM and its drug models biosimulate how specific compounds or combinations affect disease pathways, producing a therapy response prediction that can guide treatment selection. The CBM has been validated across multiple clinical datasets, with findings featured in more than 125 peer-reviewed presentations and publications in collaboration with global partners.

About Cellworks Group

Cellworks Group, Inc. is dedicated to improving patient outcomes by harnessing the power of computational science to deliver Personalized Therapy Decision Support and Best-in-Class PTRS solutions. The Cellworks Platform predicts patient-specific therapy response for oncology and other serious diseases using a breakthrough Computational Biology Model (CBM) and biosimulation technology. Cellworks is backed by Artiman Ventures, Bering Capital, Sequoia Capital, UnitedHealth Group and Agilent Ventures. Headquartered in South San Francisco, the company also operates a CLIA-certified computational lab in Franklin, Tennessee. Learn more at www.cellworks.life.

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