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MASTL regulates EGFR signaling to impact pancreatic cancer progression

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.

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Fig. 1: MASTL expression correlates with pancreatic cancer (PC).
Fig. 2: MASTL knockdown (MKD) alters cellular functions to regulate PC cells.
Fig. 3: MASTL inhibition significantly inhibits tumor formation in xenograft model in vivo.
Fig. 4: Greatwall kinase inhibitor (GKI-1) inhibited MASTL expression and altered functional characteristics in PC cell lines in vitro.
Fig. 5: Anti-tumorigenic potential of GKI-1 was analyzed on tumor xenograft in in vivo.
Fig. 6: MASTL mediates its effect through the regulation of EGFR/Galectin-1/Survivin/Bcl-xl signaling.
Fig. 7: MASTL expression correlates directly with EGFR expression in pancreatic cancer.
Fig. 8: EGFR overexpression in tHPNEMKD and Capan-1MKD cells abrogated the effects of MASTL inhibition on cell survival and downstream signaling.
Fig. 9: MASTL expression enhances chemoresistance through EGFR/Survivin pathway.

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Acknowledgements

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.

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PD, IF and SB conceived the study and participated in the study design, performance, coordination and manuscript writing. IF. SB, JPU, SC, SR1, SR2, MPP, LS, GT carried out the assaysand analysis. ABS and SKB revised the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Punita Dhawan.

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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

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