MASTL: A novel therapeutic target for Cancer Malignancy

Abstract

Targeting mitotic kinases is an emerging anticancer approach with promising preclinical outcomes. Microtubule‐associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl), is an important mitotic kinase that regulates mitotic progression of normal or transformed cells by blocking the activity of tumor suppressor protein phosphatase 2A (PP2A). MASTL upregulation has now been detected in multiple cancer types and associated with aggressive clinicopathological features. Apart, an aberrant MASTL activity has been implicated in oncogenic transformation through the development of chromosomal instability and alteration of key oncogenic signaling pathways. In this regard, recent publications have revealed potential role of MASTL in the regulation of AKT/mTOR and Wnt/β‐catenin signaling pathways, which may be independent of its regulation of PP2A‐B55 (PP2A holoenzyme containing a B55‐family regulatory subunit). Taken together, MASTL kinase has emerged as a novel target for cancer therapeutics, and hence development of small molecule inhibitors of MASTL may significantly improve the clinical outcomes of cancer patients. In this article, we review the role of MASTL in cancer progression and the current gaps in this knowledge. We also discuss potential efficacy of MASTL expression for cancer diagnosis and therapy.

Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers

“…The kinase MAP3K2 (MEKK2) activates the MEK5/ERK5 cell signaling pathway and is thought to play an important role in tumor growth and metastasis 1 . MASTL, or microtubule-associated serine/threonine kinase like, is an important mitotic kinase that regulates mitotic progression of normal or transformed cells by blocking tumor suppressor protein phosphatase 2A (PP2A) activity, where MASTL deregulation has been detected in multiple cancer types and associated with aggressive clinicopathological features 24 . The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation, with functional roles demonstrated for multiple cancer types 28 .…”

“…The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation, with functional roles demonstrated for multiple cancer types 28 . Inhibitors exist for MAP3K2, MASTL, and TTK 1 , 24 , 28 . Previously studied in other cancer types, these kinases may represent therapeutic targets for uterine endometrial cancer in particular.…”

Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes

“…Although recent studies suggest that MASTL is a promising target for selective anticancer treatment [ 16 ], MASTL inhibitors with nM range potency and antitumor efficacy have not been reported. Our previous report showed that MKI-1 was an MASTL inhibitor with antitumor activities in breast cancer cells.…”

“…Recent studies suggested that MASTL acts as an oncogenic kinase by inactivating tumor suppressive PP2A-B55 complex in breast cancer cells [11][12][13], thereby regulating various oncogenic properties, such as cellular transformation, chromosome instability, and Pharmaceuticals 2021, 14, 647. https://doi.org/10.3390/ph14070647 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 647 2 of 12 metastasis [3,14,15]. MASTL targeting has reduced tumor growth in various in vitro and in vivo tumor models [13,16]. Notably, MASTL are highly expressed in multiple types of cancers, including breast, head and neck, gastric, thyroid, and colorectal cancers [12,15,[17][18][19][20].…”

Insights of RKIP-Derived Suppression of Prostate Cancer

“…In comparison to wild type mice, GSK3β expression is significantly reduced in the prostate epithelial cells of RKIP −/− mice [ 81 ], supporting the regulation being physiologically relevant. GSK3β possesses tumor suppressing function via inhibiting the Wnt/β-catenin pathway [ 83 ], EMT, and cyclin D1 expression [ 81 ].…”