Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells.

Melanoma cells are highly resistant to anoikis, a form of apoptosis induced in nonadherent/inappropriate adhesion conditions. Depleting B-RAF or the prosurvival Bcl-2 family protein Mcl-1 renders mutant B-RAF melanoma cells susceptible to anoikis. In this study, we examined the effect of targeting B-RAF on the survival of primary stage melanoma cells cultured in three-dimensional type I collagen gels, which partially mimics the dermal microenvironment. Depletion/inhibition of B-RAF with small interfering RNA or the mutant B-RAF inhibitor, PLX4720, induced apoptosis of mutant B-RAF melanoma cells in three-dimensional collagen. Apoptosis was dependent on two upregulated BH3-only proteins, Bim-EL and Bmf, and was inhibited by ectopic Mcl-1 expression. Akt3 activation has been associated with the survival of melanoma cells. Mutant B-RAF melanoma cells ectopically expressing a constitutively activated form of Akt3 or endogenously expressing mutant Akt3 were protected from apoptosis induced by B-RAF knockdown or PLX4720 treatment. Furthermore, intrinsically resistant metastatic melanoma cells displayed elevated Akt phosphorylation in three-dimensional collagen and were rendered susceptible to PLX4720 by Akt3 knockdown. Importantly, myristylated Akt3 prevented B-RAF targeting-induced upregulation of Bim-EL and Bmf in three-dimensional collagen and partially protected Mcl-1-depleted cells from apoptosis. These findings delineate how mutant B-RAF protects melanoma cells from apoptosis and provide insight into possible resistance mechanisms to B-RAF inhibitors.

Shao Y ，Aplin AE 《-》

PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression.

Paraiso KH ，Xiang Y ，Rebecca VW ，Abel EV ，Chen YA ，Munko AC ，Wood E ，Fedorenko IV ，Sondak VK ，Anderson AR ，Ribas A ，Palma MD ，Nathanson KL ，Koomen JM ，Messina JL ，Smalley KS ... -  《-》

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma.

Shao Y ，Aplin AE 《-》

Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS.

Jiang CC ，Lai F ，Tay KH ，Croft A ，Rizos H ，Becker TM ，Yang F ，Liu H ，Thorne RF ，Hersey P ，Zhang XD ... -  《Cell Death & Disease》

Mcl-1 is required for melanoma cell resistance to anoikis.

Boisvert-Adamo K ，Longmate W ，Abel EV ，Aplin AE ... -  《MOLECULAR CANCER RESEARCH》