Abstract 2541: Mastl regulates EGFR signaling to promote pancreatic cancer progression
Authors: Fatima Iram , Chauhan Shailender S. , Uppada Srijayaprakash Babu , Talmon Geoffrey A. , Singh Amar B. , Batra Surinder K. , Dhawan Punita 
Published: August 2019

Background: Anti-cancer treatments act primarily by damaging the DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Hence, pharmacological inhibition of checkpoint kinases in combination with the DNA damaging anti-cancer therapies is now emerging as promising cancer treatment strategy. In this regard, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with a frightening resistance to chemotherapeutic and targeted approaches. Here, along with the KRAS-dependent signaling, receptor tyrosine kinases especially the EGF receptor (EGFR) signaling is strongly upregulated in PDAC. Importantly, Greatwall (Mastl; Microtubule-associated serine/threonine-protein kinase-like) promotes normal G2-mitosis transition and is highly upregulated in multiple cancer types, and have been demonstrated to associate with therapy resistance. However, potential role of Mastl in pancreatic cancer progression/therapy resistance remains unknown. Our central hypothesis is that MASTL expression is (a) involved in cancer progression and intrinsic drug resistance (b) constitutes a potential therapeutic target for PDAC (c) correlates with EGFR expression and regulation.

Methods: We used immunoblotting, immunohistochemistry and TCGA database analysis to examine Mastl expression, its association with EGFR in pancreatic cancer progression, and patient survival. Genetic and pharmacological manipulations for Mastl expression were performed and effects on proliferation, apoptosis and cell cycle were determined.

Results: A robust increase in Mastl expression characterized pancreatic cancer cells when compared with the non-transformed pancreatic cells. A similar upregulated expression of Mastl was found in samples originating from KPC mouse model of PDAC. Analysis of the human pancreatic cancer samples and the TCGA database strongly supported this outcome and suggested a positive association of the Mastl expression with cancer progression and patient mortality. Interestingly, genetic inhibition of Mastl expression in pancreatic cancer cells not only inhibited the ability of these cells to proliferate and invade through the matrix but also inhibited activation of the ErbB-family of tyrosine kinase receptors. Further studies revealed that overexpressing K-ras/mutant p53 pathway in HPNE cells (untransformed pancreatic cells) modulates Mastl expression, and thus suggested a causal correlation of Mastl with K-Ras/EGFR signaling in pancreatic cancer cells.

Conclusion: Our results suggest a cross talk of Mastl with K-ras/EGFR signaling pathway in pancreatic cancer progression. We hypothesize that combinatorial therapy targeting Mastl along with Gemcitabine would overcome the drug resistance in the PDAC. Thus, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

Citation Format: Iram Fatima, Shailender S. Chauhan, Srijayaprakash Babu Uppada, Geoffrey A. Talmon, Amar B. Singh, Surinder K. Batra, Punita Dhawan. Mastl regulates EGFR signaling to promote pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2541.