International study signposts promising therapeutic strategy to prevent resistance to RAF-MEK inhibitors

  • A study published in this month´s Nature Genetics, in which the Vall d’Hebron Institute of Oncology (VHIO) participated, has revealed a parallel pathway driving cancer cell resistance to RAF-MEK inhibitors
  • This finding signposts a new therapeutic strategy aimed at improving cellular response to this targeted anti-cancer therapy with better outcomes for patients

Barcelona, February 10, 2015. Findings reported yesterday in Nature Genetics* have revealed YAP as a parallel pathway implicated in resistance to RAF-MEK inhibitor target-based therapies. The multicenter study, in which both Javier Cortés and Eva Muñoz from the Vall d’Hebron Institute of Oncology (VHIO) participated, demonstrates the clinical potential of inhibiting YAP, along with RAF-MEK, to improve cellular response to targeted therapy and therefore, better outcomes for patients.

Resistance to RAF-MEK inhibitor-targeted therapy represents a major challenge in oncology. While many tumors initially respond to potent anti-cancer treatments, with time, they acquire resistance and therapy ceases to be effective. This is often the case for patients with RAS or BRAF mutations.

This international study, in which several Spanish researchers and groups participated, reveals how the YAP pathway conspires in cancer cell resistance to RAF-MEK inhibitors, helping these cells to survive and dodge powerful cancer therapeutics. This latest discovery demonstrates the potential of adding a YAP inhibitor to the already established RAF-MEK inhibitor mix — the latter being lethal weaponry against cancer cells in several tumor types harboring the BRAF mutation as well as in RAS-mutant tumors.

Another major finding, demonstrating the clinical relevance of this study, was establishing increased levels of YAP as a biomarker of response in patients with BRAF mutations.

“With higher levels of YAP, there is a worse initial response to targeted therapy with RAF inhibitors, explains Javier Cortés, co-author of the study, and Principal Investigator of VHIO´s Breast Cancer and Melanoma Group.

Having identified YAP as a co-culprit implicated in driving resistance to RAF- and MEK -targeted therapies, the study proposes the collective inhibition of YAP and RAF-MEK as a promising new therapeutic strategy aimed at eliminating these pathways, preventing resistance, improving treatment response as well as, ultimately, patient survival.


* The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies, Nature Genetics (2015) doi:10.1038/ng.3218

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