RT Journal Article
SR Electronic
T1 Distinct Transcriptional Programming Drive Response to MAPK Inhibition in <em>BRAF</em><sup>V600</sup>-Mutant Melanoma Patient-Derived Xenografts
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2421
OP 2432
DO 10.1158/1535-7163.MCT-19-0028
VO 18
IS 12
A1 Feng, Tianshu
A1 Golji, Javad
A1 Li, Ailing
A1 Zhang, Xiamei
A1 Ruddy, David A.
A1 Rakiec, Daniel P.
A1 Geyer, Felipe C.
A1 Gu, Jane
A1 Gao, Hui
A1 Williams, Juliet A.
A1 Stuart, Darrin D.
A1 Meyer, Matthew J.
YR 2019
UL http://mct.aacrjournals.org/content/18/12/2421.abstract
AB Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAFV600-mutant melanoma. However, the duration and depth of response vary significantly between patients; therefore, predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of an MITF-high, “epithelial-like” transcriptional program is associated with reduced sensitivity and adaptive response to BRAF and MEK inhibitor treatment. On the other hand, xenograft models that express an MAPK-driven “mesenchymal-like” transcriptional program are preferentially sensitive to MAPK inhibition. These gene-expression programs are somewhat similar to the MITF-high and -low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with drug response. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAFV600-mutant melanoma relies on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predicts their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the intertumor heterogeneity in BRAFV600-mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.