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BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells

Kan He1,2, Dongshi Chen2,3, Hang Ruan1,2

  • 1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Oncotarget
|June 29, 2016
PubMed

Insights

BRAF V600E mutations cause resistance to mTOR inhibitors in colon cancer by activating ERK and Mcl-1. Combining mTOR inhibitors with Mcl-1, PI3K, RAF, or MEK inhibitors can restore apoptosis in these resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mammalian target of rapamycin (mTOR) pathway activation, driven by oncogenic mutations in RAS/RAF/MAPK and PI3K/AKT pathways, is crucial for cancer progression and therapeutic resistance.
  • Despite their role in suppressing tumor growth and angiogenesis, mTOR inhibitors exhibit limited efficacy as single agents in patients.
  • mTOR inhibitors have recently been shown to induce apoptosis in colon cancers, but resistance mechanisms remain a challenge.

Purpose of the Study:

  • To investigate the role of BRAF V600E mutations in conferring resistance to mTOR inhibitors in colorectal cancer.
  • To elucidate the molecular mechanisms by which BRAF V600E leads to resistance against mTOR inhibitors.
  • To identify potential combination therapies to overcome mTOR inhibitor resistance in BRAF V600E-mutated colorectal cancer.

Main Methods:

  • Utilized a panel of BRAF V600E and wild-type (WT) colorectal cancer cell lines and in vitro selected resistant cultures.
  • Employed xenograft models to assess the efficacy of mTOR inhibitors and combination therapies in vivo.
  • Investigated the effects of everolimus on signaling pathways, including ERK and Mcl-1, and their interaction with the death receptor pathway.

Main Results:

  • Demonstrated that BRAF V600E mutations confer resistance to mTOR inhibitors in colorectal cancer.
  • Showed that everolimus treatment disrupts the S6K1-IRS-2/PI3K negative feedback loop, leading to BRAF V600E-dependent activation of ERK and Mcl-1 stabilization.
  • Established that ERK and Mcl-1 stabilization blocks death receptor-mediated apoptosis by inhibiting crosstalk to mitochondria.

Conclusions:

  • BRAF V600E-driven activation of ERK and Mcl-1 is a key mechanism of resistance to mTOR inhibitors in colon cancer.
  • Co-treatment strategies involving Mcl-1, PI3K, RAF, or MEK inhibitors can restore mTOR inhibitor-induced apoptosis in BRAFV600E colorectal cancer.
  • Findings support genotype-guided patient stratification and the development of rational drug combinations to enhance mTOR inhibitor therapy.
Keywords:
BRAF V600EERKMcl-1everolimusmTOR

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