The BH3 mimetic ABT-737 sensitises human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance
Menée sur des lignées cellulaires, cette étude suggère que l'ajout d'un composé appelé ABT-737, un inhibiteur BH3 mimétique ciblant des protéines de la famille Bcl-2, à un inhibiteur de BRAF pourrait améliorer la réponse thérapeutique initiale chez des patients atteints d'un mélanome présentant une mutation V600E du gène BRAF, mais n'aurait pas d'effet chez les patients dont les tumeurs sont devenues résistantes au traitement
Although the introduction of selective BRAF inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilisation of disease or no response at all. The present study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. We examined the influence of the BH3 mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 in melanoma cells with or without BRAF V600E mutation. Included were cell lines established from four patients before and during treatment with selective BRAF inhibitors and 3D spheroids derived from these cell lines. Cell lines with no or low sensitivity to PLX4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT-737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following siRNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors and in 3D spheroids derived from these cell lines. These results suggest that combination of selective BRAF inhibitors with ABT-737 or the related orally available compound ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents.
http://carcin.oxfordjournals.org/content/early/2012/10/19/carcin.bgs330.abstract