2. Academic Validation
  3. Focal Adhesion Kinase Intersects With the BRD4-MYC Axis and YAP1 to Drive Tumor Cell Growth, Phenotypic Plasticity, Stemness, and Metastatic Potential in Colorectal Cancer

Focal Adhesion Kinase Intersects With the BRD4-MYC Axis and YAP1 to Drive Tumor Cell Growth, Phenotypic Plasticity, Stemness, and Metastatic Potential in Colorectal Cancer

  • Cancer Med. 2025 Sep;14(18):e71227. doi: 10.1002/cam4.71227.
Rongbo Han 1 2,  Junfeng Shi 3,  Kai Cheng 4,  Zian Wang 5,  Yecang Chen 1,  Orion Spellecy 1,  Abu Saleh Mosa Faisal 6,  Isha Aryal 1,  Jinfei Chen 7,  Rolf Craven 1,  Olivier Thibault 1,  Lauren Baldwin 6,  Lawrence D Brewer 1,  Sonia Erfani 1 8,  Chi Wang 6,  Zhenheng Guo 1,  Eric Chen 9,  Burton Yang 10,  Frederick Ueland 6,  Ruihua Guo 5,  Xiuwei Yang 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
  • 2 Department of Oncology, The Fourth Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
  • 3 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
  • 4 Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, China.
  • 5 College of Food Science and Technology, Shanghai Ocean University, Shanghai, China.
  • 6 Markey Cancer Center and Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
  • 7 Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 8 Pharmacy Services, University of Kentucky Medical Center, Lexington, Kentucky, USA.
  • 9 Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.
  • 10 Department of Laboratory Medicine and Pathobiology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
PMID: 40959971 DOI: 10.1002/cam4.71227
Abstract

Objective: Colorectal Cancer (CRC) remains one of the leading causes of cancer-related death worldwide due to the lack of effective therapies. Here we explored the clinical basis and therapeutic promise of the integrin-focal adhesion kinase (FAK)-dependent pathway for CRC.

Methods and results: Our bioinformatic and histological analyses showed that FAK was markedly upregulated at both mRNA and protein and signaling levels in the two CRC patient cohorts. Particularly, the portion of carcinomas carrying active FAK (Y397phosphorylation) increased by threefold from stage I to III/IV tumors or metastatic lesions. Consistent with this clinic landscape, FAK inhibition via knockdown or chemical inhibitors suppressed tumor cell growth largely in the subset of CRC cell lines with low MYC expression. In contrast, the FAK inhibition was less effective in the cell line pool with high MYC expression. The resistance to FAK targeting diminished upon a co-inhibition of BRD4 via BET inhibitors. It coincided with an induction of cell cycle arrest at G1-S and G2-M phases, elevated Apoptosis and chemosensitivity (paclitaxel and oxaliplatin), and impaired stemness. Mechanistically, the BET inhibitor induced an EMT-like phenotype, tilting tumor cell dependence toward the integrin-FAK axis. Moreover, inhibiting FAK alone or in combination with Src or BRD4 markedly suppressed cell motility and the YAP or MYC activation, and restored the expression of the long isoform BRD4. Also, co-genomic/genetic dysregulations of FAK and YAP1 or Src strongly correlated with poor disease-free patient survival.

Conclusion: Overall, our study highlights the potent pro-malignant role of the integrin-FAK axis in CRC, fueling its targeting as a single agent or synthetic lethal-based therapy.

Keywords

BRD4; FAK; MYC; colorectal cancer; metastasis; tumor growth.

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