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Updated: May 20, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Ravid Straussman1, Teppei Morikawa, Kevin Shee

  • 1The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

Nature
|July 6, 2012
PubMed

Insights

The tumor microenvironment, not just cancer cells, causes drug resistance. Stromal cells secrete factors like hepatocyte growth factor (HGF) that block cancer drug effectiveness, suggesting combination therapies targeting both cancer and stromal cells.

Area of Science:

  • Oncology
  • Cancer Biology
  • Tumor Microenvironment Research

Background:

  • Drug resistance in cancer patients is a significant clinical challenge.
  • Most research focuses on intrinsic cancer cell resistance mechanisms.
  • The tumor microenvironment's role in conferring innate drug resistance is increasingly recognized.

Purpose of the Study:

  • To investigate the influence of various stromal cell types on cancer cell drug resistance.
  • To identify specific mechanisms by which the tumor microenvironment mediates resistance to anticancer drugs.
  • To explore novel therapeutic strategies for overcoming stroma-mediated drug resistance.

Main Methods:

  • Development of a co-culture system to test 23 stromal cell types against 45 cancer cell lines and 35 drugs.
  • Proteomic analysis to identify molecular mediators of resistance.
  • Immunohistochemistry to validate findings in patient samples.
  • Inhibition studies to assess therapeutic potential.

Main Results:

  • Stromal cells commonly confer innate resistance to anticancer drugs, especially targeted agents.
  • Hepatocyte growth factor (HGF) secreted by stromal cells activates MET, reactivating MAPK and PI(3)K-AKT pathways, leading to immediate resistance to RAF inhibitors in BRAF-mutant melanoma.
  • Stromal HGF expression correlates with innate resistance to RAF inhibitors in patients.
  • Similar resistance mechanisms were observed in BRAF-mutant colorectal and glioblastoma cell lines.

Conclusions:

  • The tumor microenvironment plays a critical role in mediating innate drug resistance.
  • Targeting stromal factors like HGF or its receptor MET, in combination with RAF inhibitors, can overcome drug resistance in BRAF-mutant melanoma.
  • Systematic analysis of tumor-stroma interactions is crucial for uncovering drug resistance mechanisms and developing effective cancer therapies.

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