2. Academic Validation
  3. Identification of the MRTFA/SRF pathway as a critical regulator of quiescence and chemotherapy resistance in cancer

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

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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