BRAF mutation confers TGF-? addiction
Session type: Poster / e-Poster / Silent Theatre session
TGF-? acts as a tumour suppressor in normal epithelial cells and during early stage tumourigensis. During malignant progression some tumours switch their response to TGF-? and paradoxically utilise this factor as a potent promoter of disease but the mechanistic basis for this is poorly understood. Consequently defining how, when and where TGF-? acts in a pro-tumourigenic fashion is pivotal to both the design and implementation of TGF-? targeted therapy.
Using a panel of human tumour cell lines with defined mutational status of BRAF, NRAS, KRAS and HRAS we have investigated the contribution of TGF-? signalling to cell proliferation in vitro and in vivo employing siRNA and inhibitor based strategems.
Here we demonstrate that V600E mutation of BRAF, a frequent driving mutation in human cancer, diverts TGF-? from inhibiting to promoting cell proliferation. Mechanistically, autocrine TGF-? signals through activin like kinase 5 (ALK5) to activate RhoA and suppress p21 accumulation to enable anchorage-independent growth in vitro and tumour growth in vivo. Using small molecule inhibitors of ALK5 we find that BRAF mutant human tumour cell lines are dependent on ALK5 regardless of the tissue of origin. Conversely, ALK5 inhibitors stimulate the proliferation of many wild-type cell lines or cell lines harbouring a 'RAS' mutation.
These data indicate a dependency on ALK5 activity in BRAF mutant tumours, suggest a rational targeted therapy for this genetically defined subset of tumours and provide an essential stratification criterion for the use of anti-TGF-? therapeutics for cancer treatment.