MASTL regulates EGFR signaling to impact pancreatic cancer progression

Iram Fatima, Susmita Barman, Jaya Prakash Uppada, Shailender Chauhan, Sanchita Rauth, Satyanarayana Rachagani, Moorthy Palanimuthu Ponnusamy, Lynette Smith, Geoffrey Talmon, Amar B. Singh, Surinder K. Batra, Punita Dhawan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5691-5704
Number of pages14
JournalOncogene
Volume40
Issue number38
DOIs
StatePublished - Sep 23 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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