2. Academic Validation
  3. Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer

Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer

  • J Exp Clin Cancer Res. 2024 Jul 11;43(1):192. doi: 10.1186/s13046-024-03106-8.
Prachi Bajpai 1,  Sumit Agarwal 1,  Farrukh Afaq 1,  Sameer Al Diffalha 1 2,  Darshan S Chandrashekar 1,  Hyung-Gyoon Kim 1,  Abigail Shelton 1,  C Ryan Miller 1 2,  Santosh K Singh 3,  Rajesh Singh 3,  Sooryanarayana Varambally 1 2,  Ganji Purnachandra Nagaraju 4,  Ashish Manne 5,  Ravi Paluri 6,  Moh'd Khushman 7,  Upender Manne 8 9
Affiliations

Affiliations

  • 1 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 2 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 3 Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, USA.
  • 4 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 5 Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • 6 Department of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • 7 Department of Medicine, Washington University in St. Louis/Siteman Cancer Center, St. Louis, MO, USA.
  • 8 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. upendermanne@uabmc.edu.
  • 9 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. upendermanne@uabmc.edu.
PMID: 38992681 DOI: 10.1186/s13046-024-03106-8
Abstract

Background: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models.

Methods: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and Apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized.

Results: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and Other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and Apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in Apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib.

Conclusions: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.

Keywords

Colorectal cancer; Combination therapy; JAK/HDACi; Regorafenib; Toxicity.

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