Examination of FOXP1 in SCLC Yields Potential Strategy Against Chemoresistance

The transcription factor appears to play an important role in chemoresistance in patients with small cell lung cancer (SCLC), a new study has found.

Writing in the journal Communications Biology, the authors of the study said they believe their findings point to a potential new therapeutic strategy for patients with chemotherapy resistance.¹

In SCLC, transcription factors have also been found to play a key role in chemoresistance, and differences in expression of transcription factors have been tied to drug sensitivities. | Image credit: Rasi-stock.adobe.com

SCLC is a notoriously aggressive form of cancer. A 2021 analysis of the US Surveillance, Epidemiology, and End Results (SEER) database found that between 1983 and 2012, the median survival was just 7 months.² And while new CT screening guidelines have reduced the mortality rate for lung cancer generally, the study found no such effect was occurring in SCLC, despite a marginal improvement in the 5-year mortality rate.

In the new report, corresponding author Linlang Guo, MD, PhD, of China’s Southern Medical University, and colleagues, noted that surgery is usually not feasible in advanced cases of SCLC.¹ Instead, chemotherapy with or without radiation is the standard treatment. However, while an estimated 60-70% of patients will initially respond to therapy, acquired resistance is common, resulting in the cancer type’s very poor prognosis.³

Guo and colleagues said immunotherapies are being investigated that might help improve outcomes for these patients.¹ In the meantime, though, they noted that chemoresistance remains a major unsolved problem.

In an effort to solve the problem, they looked at the role of transcription factors. Transcription factors have long been implicated in the development and progression of cancer. In SCLC, transcription factors have also been found to play a key role in chemoresistance, and differences in expression of transcription factors have been tied to drug sensitivities, the authors said.

Phase separation, meanwhile, has been linked with drug resistance in tumors by promoting transcriptional irregularities in tumor cells, they noted.

“However, the role of phase separation in SCLC has not been reported, nor has the role of phase separation in the transcription factors associated with chemotherapy resistance in SCLC,” they wrote.

In previous research, the investigators identified FOXP1 as one of 3 key master transcription factors in the chemoresistant SCLC cell line H69AR. However, of those 3, only FOXP1 expression was found to be significantly elevated in patient samples of relapsed SCLC.

“This suggests a potential link between FOXP1 and chemotherapy resistance in SCLC,” the authors wrote.

In their new analysis, Guo and colleagues found that FOXP1 enhances chemoresistance by regulating SP8 expression. The regulation occurs through SP8’s super-enhancer. SP8, meanwhile, mediates resistance via the homologous recombination repair (HRR) pathway.

“We also discovered that FOXP1 forms punctate nuclear structures indicative of liquid-liquid phase separation, crucial for its transcriptional regulation,” they said.

The investigators then examined the clinical implications of their findings. They proposed combining BET inhibitors and PARP inhibitors in patients with chemotherapy-resistant SCLC.

In the study, the authors said using the 2 inhibitors to target the FOX1-SP8-HR axis had synergistic effects, reducing tumor growth both in vitro and in patient-derived xenograft models.

“Overall, this study is the first to validate the presence of phase isolation of the transcription factor FOXP1 in SCLC and demonstrate that it is associated with chemotherapy resistance and mediates a downstream homologous recombination repair pathway,” Guo and colleagues said.

Still, while the authors said their proposed combination represents a new treatment opportunity in chemotherapy-resistant SCLC, they said they could not rule out the potential involvement of other mechanisms. Thus, they said, further research is needed.

References

1. Tang Y, Niu Y, Chen Y, et al. Targeting FOXP1 phase separation in small cell lung cancer mechanisms of chemotherapy resistance. Commun Biol. 2025;8(1):431. doi:10.1038/s42003-025-07804-7
2. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. doi:10.1038/s41572-020-00235-0
3. Herzog BH, Devarakonda S, Govindan R. Overcoming Chemotherapy Resistance in SCLC. J Thorac Oncol. 2021;16(12):2002-2015. doi:10.1016/j.jtho.2021.07.018