Erk inhibitors intercept Erk-mediated negative feedback while imposing cell-cycle arrest and activating p38.

Authors

Merav Darash-Yahana, Nadine Soudah, Alexey Baskin, Inbal Levy-Saar, Alexander Levitzki, David Engelberg

Published in

iScience. Volume 29. Issue 7. Pages 116629. Jul 17, 2026. Epub Jul 07, 2026.

Abstract

The MAP kinases Erk1/2 mediate the oncogenicity of the receptor tyrosine kinase (RTK)-Ras-Raf-MEK cascade. Components of this pathway are often constantly active in cancer, making Erks promising targets for therapy. Yet, while Erks promote cell proliferation, they concomitantly inhibit the upstream pathway's components. Erks' inhibition may reactivate, therefore, proto-oncoproteins, increasing the risk of recurrent disease. We studied the effects of Erks' inhibitors on cells transformed by Erk1^R84H or Erk1^R84S, and on 9 cancer-derived cell lines. Provision of either BVD523, GDC0994, SCH772984, ASN007, or Temuterkib, led to strong phosphorylation of Erks, suggesting that all inhibitors intercepted Erks-mediated negative feedback activity. All inhibitors caused cell-cycle arrest at G1 and activation of the MAP/stress kinase p38, but some degree of cell viability was maintained even after 72 h of treatment. Exposure to BVD523 caused dramatic changes in the phosphoproteome. Thus, the application of Erk's inhibitors should be accompanied by agents that prevent pathway re-activation.

PMID:
42438827
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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