MASTL regulates EGFR signaling to impact pancreatic cancer progression

• Published in: Oncogene 2021-09, Vol.40 (38), p.5691-5704
• Main Authors: Fatima, Iram, Barman, Susmita, Uppada, JayaPrakash, Chauhan, Shailender, Rauth, Sanchita, Rachagani, Satyanarayana, Ponnusamy, Moorthy Palanimuthu, Smith, Lynette, Talmon, Geoffrey, Singh, Amar B., Batra, Surinder K., Dhawan, Punita
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/2; 38/89; 42/109; 45/41; 45/77; 631/67/1059/2326; 631/67/1504/1713; 96/106; Animal models; Animals; Antitumor agents; Apoptosis; Cancer therapies; Care and treatment; Cell Biology; Cell Line, Tumor; Cellular signal transduction; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Development and progression; Disease Progression; Epidermal growth factor; ErbB Receptors - chemistry; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gain of Function Mutation; Gemcitabine; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Immune checkpoint; Internal Medicine; Kinases; Loss of Function Mutation; Malignancy; Medicine; Medicine & Public Health; Mice; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Neoplasm Transplantation; Oncology; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein kinase; Protein kinases; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Stability; Signal Transduction - drug effects; Threonine; Up-Regulation - drug effects
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01951-x

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.