Journal: Cancer research

Article Title: Src-dependent DBL family members drive resistance to vemurafenib in human melanoma

doi: 10.1158/0008-5472.CAN-19-0244

Figure Lengend Snippet: (A) The resistance driven by MCF2 and VAV1 can be overcome with the addition of saracatinib. However, saracatinib cannot block resistance driven by the expression of truncated BRAFV600E or RAF1 [*adjusted p-value < 0.05 relative to vemurafenib alone]. (B) The addition of saracatinib does not uniformly increase vemurafenib response in a panel of BRAFV600E mutant human melanoma cell lines [*adjusted p-value < 0.0001]. (C) Saracatinib, but not imatinib, is able to induce cytotoxicity with vemurafenib in A375 cells. (D) The addition of saracatinib is able to induce cytotoxicity in cells that have acquired spontaneous resistance to vemurafenib. Saracatinib treatment reverses the increase in RAC1-GTP (E) and CDC42-GTP (F) observed in A375 cells expressing MCF2 and VAV1. (G) The resistance candidates perform differently in response to treatment with LY3009120, a next generation Raf inhibitor. Importantly, the combination of LY3009120 and saracatinib is cytotoxic to all cell populations (note independent y-axes).

Article Snippet: Unless otherwise indicated, inhibitors and the concentration used in these experiments include vemurafenib (5 µm; Selleckchem), cobimetinib (5 nm; Selleckchem), saracatinib (1 or 2 µm; Selleckchem;), FRAX-486 (50 nm; Selleckchem), Fasudil (7 or 10 µm; Sigma), LY3009120 (Selleckchem; 1 µm), Imatinib (2 µm; Cayman Chemical), ulixertinib (3 µM; Selleckchem), dabrafenib (200 nM; Selleckchem), encorafenib (500 nM; Selleckchem), trametinib (2 nM; Selleckchem), binimetinib (50 nM; Selleckchem).

Techniques: Blocking Assay, Expressing, Mutagenesis