Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Abstract

Therapies targeting tyrosine and serine/threonine kinases have raised enormous interest as potential cure for cancer patients in many common cancer types. However, except for the success story with BCR/ABL tyrosine kinase inhibitors in chronic myeloid leukemia (CML), critical review of results of a large number of clinical trials indicates that the clinical success with kinase inhibitors has been overall disappointing. These alarming results call for critical assessment of whether there is some fundamental flaw in the design of strategies to target phosphorylation-dependent oncogenic signaling for cancer therapy. This viewpoint debates on one potential, but thus far largely neglected, molecular explanation why inhibition of protein kinases is not sufficient for cancer cure. We note that the phosphorylation status, and thus the oncogenic potential of any given protein, is not regulated only by kinases, but rather by an intimate balance between kinases and their antagonist phosphatases. We further review the supporting functional evidence that for oncogenic transformation of human cells it is not enough to activate kinase signaling by activated kinases, if a group of counteracting tumor suppressor phosphatases is not inactivated. Based on these considerations, and a very recently emerged role of oncogenic function of a group of phosphatase inhibitor proteins as human oncoproteins, we propose that in order to efficiently inhibit phosphorylation-dependent signaling in cancer cells, and thus provide better therapeutic index, the kinase inhibitors should be combined with strategies to reactivate tumor suppressor phosphatases such as Protein Phosphatase 2A (PP2A).

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

“…Reversible phosphorylation allows the cell to maintain a proper homeostasis regulation; therefore, the balance between kinases and phosphatases is essential to control correct proliferation, apoptosis, and differentiation. Many studies have analyzed the abnormal behavior of protein kinases in AML, but the role of phosphatases remains underexplored 11,12 . Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates several essential cell functions and counteracts most of the kinase-driven intracellular signaling pathways 13 .…”

Dynamic characteristics rather than static hubs are important in biological networks

“…Coupling kinase and phosphatase inhibitors have already been suggested in literature to prevent known insurgence of resistance of MEK and RAF inhibitors (Westermarck, 2018). Furthermore, this idea is supported by findings showing that PP2A status impacts the response to MAPK inhibitors (Kauko et al, 2018).…”

Inherited duplications ofPPP2R3Bpromote naevi and melanoma via a novelC21orf91-driven proliferative phenotype

“…PP2A operates via key effector pathways RAS/MAPK, Wnt and AKT/mTOR 28,29 . As such, PP2A activity is intimately involved in malignancy and response to treatments 33 , and is a major focus of potential therapeutics [33][34][35][36] .…”