Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells

Related Experiment Video

Updated: Mar 12, 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

6.6K

Lindsay C Spender1,2, G John Ferguson1,3, Sijia Liu4

  • 1Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.

Oncotarget
|November 12, 2016
PubMed

Insights

Targeting transforming growth factor-β receptor 1 (TGFBR1) inhibits melanoma cell growth and metastasis. TGFBR1 inhibition is effective even in BRAF inhibitor-resistant melanoma, offering a therapeutic strategy against drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Elevated transforming growth factor-β (TGFβ) signaling is implicated in BRAF inhibitor drug resistance.
  • The therapeutic potential of targeting TGFβ signaling in advanced melanoma remains largely unexplored.

Purpose of the Study:

  • To investigate the role of TGFβ/TGFβ receptor 1 (TGFBR1) signaling in melanoma.
  • To evaluate TGFBR1 inhibition as a therapeutic strategy for BRAF inhibitor-resistant melanoma.

Main Methods:

  • Assessed TGFβ/TGFBR1 signaling dependence in murine melanocytes with mutant BRAFV600E.
  • Utilized pharmacological TGFBR1 inhibition in human BRAF mutant melanoma cells and zebrafish xenografts.
  • Investigated combination therapy with BRAF and TGFBR1 inhibitors, including a vemurafenib analogue (PLX-4720).

Main Results:

  • Mutant BRAFV600E melanocytes showed intrinsic dependence on TGFβ/TGFBR1 signaling for clonogenicity.
  • TGFBR1 inhibition blocked clonogenicity and mitosis in human melanoma cells and inhibited metastasis in zebrafish.
  • Low-dose PLX-4720 unexpectedly promoted melanoma cell proliferation, which was blocked by TGFBR1 inhibition.
  • TGFBR1 inhibition prevented SRC phosphorylation, a marker of vemurafenib resistance.
  • Patient-derived, vemurafenib-resistant melanoma cells remained sensitive to TGFBR1 inhibition.

Conclusions:

  • TGFBR1 signaling is crucial for melanoma cell clonogenicity and metastasis.
  • TGFBR1 inhibition is a promising therapeutic strategy for advanced melanoma, including cases resistant to BRAF inhibitors.
  • Targeting TGFBR1 may overcome or prevent BRAF inhibitor drug resistance by inhibiting pathways like SRC phosphorylation.
Keywords:
BRAFPLX-4720TGF-betamelanomavemurafenib

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