Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown. Based on a comprehensive investigation involving PC patient samples, murine models of PC progression (Kras;PdxCre-KC and Kras;p53;PdxCre-KPC), and loss and gain of function studies, we report a previously undescribed critical role of MASTL in promoting cancer malignancy and therapy resistance. Mechanistically, MASTL promotes PC by modulating the epidermal growth factor receptor protein stability and, thereupon, kinase signaling. We further demonstrate that combinatorial therapy targeting MASTL promotes the efficacy of the cell-killing effects of Gemcitabine using both genetic and pharmacological inhibitions. Taken together, this study identifies a key role of MASTL in promoting PC progression and its utility as a novel target in promoting sensitivity to the anti-PC therapies.
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R Core Team 2021. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.
This study was supported by BX002086 (VA merit), CA250383 (NIH/NCI), CA216746 (NIH/NCI), and Nebraska Research Initiative (NRI) to PD and DK124095 and BX002761 (VA merit) to ABS. We also acknowledge NCI Cancer Center Support Grant P30 CA36727, NIH-1P50 CA 127297-01A2 for tissue arrays obtained.
The authors declare no competing interests.
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Fatima, I., Barman, S., Uppada, J. et al. MASTL regulates EGFR signaling to impact pancreatic cancer progression. Oncogene (2021). https://doi.org/10.1038/s41388-021-01951-x