Identification of the MRTFA/SRF pathway as a critical regulator of quiescence and chemotherapy resistance in cancer

  • Cancer Lett. 2026 May 28:646:218435. doi: 10.1016/j.canlet.2026.218435.
Santiago Panesso-Gómez  1 ,  Alexander J Cole  2 ,  Austin Arrigo  3 ,  Alex Roberts  4 ,  Maya Bello  5 ,  Alyssa Wield  6 ,  Vivian I Anyaeche  7 ,  Stacy McGonigal  8 ,  Amjad Hijazi  9 ,  Jaynish Shah  10 ,  Qi Jiang  11 ,  Tonge Ebai  12 ,  Allison C Sharrow  13 ,  George Tseng  14 ,  Euisik Yoon  15 ,  Daniel D Brown  16 ,  Amanda M Clark  17 ,  Scott D Larsen  18 ,  Ian Eder  19 ,  David Gau  20 ,  Partha Roy  21 ,  Lam Tran  22 ,  Hui Jiang  23 ,  Sara Sannino  24 ,  Jen Goeckler-Fried  25 ,  Yehyun Choi  26 ,  Jeffrey L Brodsky  27 ,  Hatice Osmanbeyoglu  28 ,  Xiaojun Ma  29 ,  Kris N Dahl  30 ,  Priscilla F McAuliffe  31 ,  Adrian V Lee  32 ,  Ronald J Buckanovich  33
Affiliations
  • 1. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 2. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 3. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 4. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 5. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 6. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 7. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 8. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 9. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 10. Australian Centre for Blood Diseases, Central Clinical School, Monash University and Alfred Health, Melbourne, VIC, Australia. Electronic address: [email protected].
  • 11. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 12. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 13. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 14. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 15. Department of Electrical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 16. Department of Chemical Engineering, Howard University, Washington, DC, USA. Electronic address: [email protected].
  • 17. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 18. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 19. Department of Bioengineering, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 20. Department of Bioengineering, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 21. Department of Bioengineering, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 22. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 23. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 24. Department of Biological Sciences, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 25. Department of Biological Sciences, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 26. Department of Electrical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 27. Department of Biological Sciences, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 28. Department of Biomedical Informatics, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 29. Department of Biomedical Informatics, University of Pittsburgh, PA, USA. Electronic address: [email protected].
  • 30. Department of Chemical Engineering, Howard University, Washington, DC, USA. Electronic address: [email protected].
  • 31. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 32. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 33. Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
PMID: 41831517 DOI: 10.1016/j.canlet.2026.218435
Abstract

Chemoresistance is a major cause of Cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single-cell culture to identify and isolate patient-derived proliferating and quiescent ovarian Cancer cells (qOvCa). RNA-seq analysis indicated that hundreds of genes that are differentially expressed in qOvCa cells are transcriptional targets of the Myocardin-Related Transcription Factor-A/Serum Response Factor (MRTFA/SRF) pathway, and both genetic disruption and pharmacologic inhibition of MRTFA/SRF interaction (with the inhibitor CCG257081) induced quiescence across multiple Cancer types. MRTFA/SRF inhibition-mediated quiescence is p27/Kip1 dependent and associated with a downregulation of cell cycle regulators, NCL, MYH9, and alterations in the Proteasome. We show that the MRTFA/SRF axis plays a dual role in chemotherapy resistance, with both pathway inhibition and activation contributing to chemotherapy resistance in vitro and in patient samples. CCG081 treatment results in a proteasome-dependent downregulation of the stem-cell marker CD133. Suggesting a critical role for the Proteasome in quiescent cells, CCG081 therapy sensitized OvCa cells to Proteasome inhibitors. In vivo, we found that CCG257081 therapy could be used to induce tumor growth-arrest and delay disease growth to improve overall survival. Moreover, we found that dual therapy with CCG081 and Proteasome inhibition further improved outcomes, leading to undetectable tumors in ∼20% of mice. Together, these data suggest that the MRTFA/SRF pathway is a critical regulator of quiescence in Cancer and a potential therapeutic target.

Keywords
CCG257081 inhibitor; Chemoresistance; Myocardin-related transcription Factor-A (MRTFA) serum response factor (SRF); Ovarian cancer; Quiescence.
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