AIF-mediated necroptosis and toxic autolysosome formation in dabrafenib/trametinib-resistant melanoma cells in combination with pazopanib, DNA damage, ATM and AMPK activation, inactivation of Hsp90, Hsp70, and GRP78 and suppression of Raf proteins (RAF-1, BRAF), anti-apoptotic proteins (Bcl-XL, Mcl-1), ERK1/2, AKT, and HDACs, prolonged survival of mice with BRAF/MEK inhibitor-resistant melanoma in combination with pazopanib. Here, HSPA5 is linked to melanoma.