TGF ‐β1 and TNF ‐α differentially regulate T wist1 mediated resistance towards BRAF / MEK inhibition in melanoma

Summary Resistance to BRAF and MEK inhibition is a common phenomenon in melanoma. Cytokines and transcription factors have been attributed to contribute to the loss of sensitivity towards these inhibitors. Here, we show that transforming growth factor ( TGF )‐β1 if combined with PLX 4032, a BRAF inhibitor, or GSK 1120212, a MEK inhibitor, substantially increased cell death in BRAF ‐mutant melanoma cell lines. This increase was based on the combined regulatory decrease in T wist1, an antiapoptotic protein. Overexpression or silencing of T wist1 attenuated or aggravated induction of apoptosis through PLX 4032 or GSK 1120212, respectively. Exposure to tumour necrosis factor ( TNF )‐α, however, led to increased T wist1 levels and oppositional decrease in cell death if exposed to PLX 4032 or GSK 1120212. This increase in drug resistance again depended on T wist1 levels. Our studies suggest that T wist1 as a common downstream target of multiple signalling cascades plays a crucial role in mediating drug resistance to BRAF ‐ and MEK ‐targeted molecular inhibitors.