MASTL Kinase in DNA Repair and Treatment Resistance in Oral Squamous Cell Carcinoma

MASTL Kinase in DNA Repair and Treatment Resistance in Oral Squamous Cell Carcinoma Abstract Microtubule Associated Serine Threonine kinase-Like (MASTL) has been shown to promote mitotic progression by suppressing protein phosphatase 2A coupled with targeting subunit B55 (PP2A/B55). Interestingly, MASTL is commonly upregulated in human cancer. In oral squamous cell carcinoma (OSCC), MASTL expression is associated with cancer progression, tumor recurrence, and adverse patient survival. Upregulation of MASTL renders OSCC cells resistant to DNA damage treatments, attenuating post-treatment cell death while promoting cell survival and proliferation. Depletion or inhibition of MASTL significantly enhanced the tumor response to cisplatin in OSCC mouse models. These findings prompt us to hypothesize that MASTL is a potentially effective drug target for OSCC therapy, especially in combination with existing chemoradiation which eliminates cancer cells via induction of DNA damage. However, the precise role of MASTL in mediating DNA damage resistance is still largely unclear; specific strategies to target MASTL kinase in cancer are lacking, representing two major hurdles to the clinical development of MASTL targeting. Our preliminary studies unveiled novel functions of MASTL in DNA repair. MASTL promotes, and B55 suppresses the repair of DNA interstrand crosslinking (ICL) caused by cisplatin. Our data also implicated the MASTL-B55 module in DNA double strand break (DSB) repair via homologous recombination (HR). In Aim 1, we will further investigate these new functions of MASTL, in the context of Fanconi anemia gene pathway that mediates ICL repair and cisplatin resistance, and Rad51- dependent HR that is of strong clinical relevance to treatment responses to chemoradiation and inhibition of poly (ADP-ribose) polymerase (PARP). In Aim 2, we will explore a novel strategy to target MASTL kinase by disrupting its C-terminal domain. This idea, supported by our preliminary data, may guide the development of new and highly selective therapeutic tools for MASTL targeting. Together, our studies will lead to new mechanistic understanding of MASTL-PP2A/B55 in DNA repair and propel the development of new therapeutic strategies to overcome treatment resistance in OSCC. Project Number: 1F31DE035010-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Odjo Gouttia | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $42,358 | Activity Code: F31 | Study Section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11165127