Open AccessMASTL regulates EGFR signaling to impact pancreatic cancer progression
Author(s) -
Iram Fatima,
Susmita Barman,
Jaya Prakash Uppada,
Shailender S. Chauhan,
Sanchita Rauth,
Moorthy P. Ponnusamy,
Lynette M. Smith,
Geoffrey A. Talmon,
Amar B. Singh,
Surinder K. Batra,
Punita Dhawan
Publication year - 2021
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-021-01951-x
Subject(s) - biology , kras , cancer , cancer research , pancreatic cancer , molecular oncology , epidermal growth factor receptor , oncogene , egfr inhibitors , cancer cell , kinase , malignancy , signal transduction , carcinogenesis , cell cycle , microbiology and biotechnology , genetics , colorectal cancer
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.