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

FEBS J. 2018 Nov;285(22):4139-4145. doi: 10.1111/febs.14617. Epub 2018 Aug 17.

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).

Keywords: AURK; EGFR; RAS; SET; SMAP; AZD6244; CIP2A; DT-061; Midostaurin; PME-1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Genes, Tumor Suppressor*
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*

Substances

  • Protein Kinase Inhibitors
  • Protein Phosphatase 2