3 DDR Phenotypes May Predict Chemotherapy Response in SCLC

Researchers identified 3 distinct DNA damage response (DDR) phenotypes in small cell lung cancer (SCLC) that may offer some insight into why some tumors respond well to frontline chemotherapy while others rapidly develop resistance.¹

These findings, published in Molecular Cancer, suggest that DDR status at diagnosis could shape tumor evolution and influence treatment outcomes.

SCLC is one of the most aggressive and hardest-to-treat lung cancers.² While most patients initially respond to chemotherapy, resistance emerges quickly, leading to disease progression. In the new study, researchers found that tumors with higher DDR activity were initially more sensitive to chemotherapy but had worse overall survival, suggesting a paradox where DNA repair mechanisms may contribute to resistance over time.¹

DNA damage response status may affect how small cell lung cancer tumors evolve after chemotherapy. | Image credit: Nattakorn – stock.adobe.com

“Together, our results suggest a model where high levels of replication stress and cell-intrinsic DNA damage drive compensatory upregulation of the DDR machinery in treatment naïve tumors, potentially priming SCLCs for resistance to DNA damaging therapies and ultimately leading to poor patient outcomes,” the authors wrote.

They analyzed tumor samples from clinical trials and model systems, categorizing them into 3 DDR clusters:

• DDR Low: least DNA repair activity, associated with poorer initial responses to chemotherapy but potentially longer survival
• DDR Intermediate: moderate DNA repair activity, showing a mix of responses
• DDR High: strongest DDR activity, associated with initially better responses but shorter overall survival

Although DDR High tumors shrank more in response to platinum-based chemotherapy, they also developed resistance quickly, suggesting DNA repair mechanisms may help tumors evade long-term treatment effects.

“Our finding that DDR High and Intermediate patients have numerically shortened overall survival following frontline chemotherapy, compared to DDR Low, may be explained by the fact that many additional lines of therapy in SCLC are also DNA-damage based.” the researchers wrote. “It is possible that as these tumors quickly develop resistance to frontline DNA-damaging therapies, they may be primed for cross-resistance to additional lines of therapy with similar mechanisms of action, a phenomena recently confirmed in SCLC.”

Tumor Evolution and Immune Evasion

The study also demonstrated a possible influence of DDR status on how tumors evolve after chemotherapy. Higher DDR activity was linked to immune evasion, meaning these tumors had lower levels of immune cell infiltration and fewer inflammatory markers, potentially making them less responsive to immunotherapy.

Some DDR Intermediate and High tumors also switched subtypes after treatment, acquiring features that should theoretically, according to the researchers, make them more vulnerable to immunotherapy. However, patients with these “inflamed” subtype switching tumors had worse overall and progression-free survival outcomes following chemoimmunotherapy compared with those with de novo SCLC-I tumors.

“When analyzing these samples further, we found these plastic tumors had some of the lowest initial immune infiltrates before treatment across a third independent cohort of treatment naïve SCLC tumors,” the researchers added. “These data suggests that DDR-specific immune cell poor microenvironments may be linked to the ability of SCLC cells to progress to an ‘inflamed’ state but not receive durable benefit from frontline chemoimmunotherapy.”

Despite these findings, the researchers acknowledged the need for larger clinical trials to validate their findings, as the current study was limited by sample size, retrospective design, lack of matched genomic profiles, and other factors.

“Our work demonstrates that initial DDR status plays a key role in shaping SCLC phenotypes and may be associated with chemotherapy response and patterns of tumor evolution following frontline therapy,” the researchers wrote. “Future work targeting DDR cluster specific phenotypes will be instrumental for ultimately improving SCLC patient outcomes.”

References

1. Morris BB, Heeke S, Xi Y, et al. DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer. Mol Cancer. 2025;24(1):90. doi:10.1186/s12943-025-02291-0
2. Lung cancer types. City of Hope. Updated May 6, 2022. Accessed March 21, 2025. https://www.cancercenter.com/cancer-types/lung-cancer/types