2. Academic Validation
  3. mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway

mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway

  • Cell Death Dis. 2026 May 6;17(1):600. doi: 10.1038/s41419-026-08836-5.
Feiyang Cai 1 2,  Fan Huang 1 2,  Christophe Goncalves 2,  Harinee Srikannan 2,  Natascha Gagnon 2,  Elizabeth M Guettler 2,  Léa Mukeba-Harchies 3,  Jennifer Maxwell 1 2,  Jie Su 2,  Krikor Bijian 2,  Fabrice Journe 3,  April A N Rose 1 2,  Alexandre Orthwein 4,  Sonia Victoria Del Rincón 5 6 7,  Wilson H Miller Jr 8 9 10
Affiliations

Affiliations

  • 1 Division of Clinical and Translational Research, McGill University, Montreal, QC, Canada.
  • 2 Lady Davis Institute, McGill University, Montreal, QC, Canada.
  • 3 Cancer Research Unit, Department of Human Biology and Toxicology, University of Mons, Mons, Belgium.
  • 4 Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 5 Division of Clinical and Translational Research, McGill University, Montreal, QC, Canada. [email protected].
  • 6 Lady Davis Institute, McGill University, Montreal, QC, Canada. [email protected].
  • 7 Department of Oncology, McGill University, Montreal, QC, Canada. [email protected].
  • 8 Division of Clinical and Translational Research, McGill University, Montreal, QC, Canada. [email protected].
  • 9 Lady Davis Institute, McGill University, Montreal, QC, Canada. [email protected].
  • 10 Department of Oncology, McGill University, Montreal, QC, Canada. [email protected].
PMID: 42091854 DOI: 10.1038/s41419-026-08836-5
Abstract

BRAF V600 inhibitors are clinically approved for the treatment of BRAFV600-mutant melanoma in combination with a MEK Inhibitor, but are ineffective in Other melanoma subtypes. Moreover, pan-RAF inhibitors, such as belvarafenib, when combined with MEK inhibitors (cobimetinib), have promising but limited efficacy in non-BRAF-mutant melanomas. Here, we report that the mTOR Inhibitor sapanisertib improves the efficacy of combined belvarafenib and cobimetinib therapy in NRAS, NF1, and KIT-mutant melanomas. Mechanistically, sapanisertib combined with belvarafenib and cobimetinib suppressed ATF4 expression and its target gene MTHFD2 while inducing DNA damage, revealing a previously underappreciated role of the ATF4-MTHFD2 axis in DNA damage repair and drug response. Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy.

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