Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts 2-4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male versus female BRAF/MEK-treated mice (p=0.006), with significantly higher expression of androgen receptor (AR) in tumors of male and female BRAF/MEK-treated mice versus control (p=0.0006 and 0.0025). Pharmacologic inhibition of AR signaling improved responses to BRAF/MEK-targeted therapy in male and female mice (p=0.018 and p=0.003), whereas induction of AR signaling (via testosterone administration) was associated with significantly impaired response to BRAF/MEK-targeted therapy in males and females (p=0.021 and p<0.0001).

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001008708	Human (n=34) and mice (n=68) melanoma tumor WXS dataset.	NextSeq 500	102

Publications	Citations
Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy. Vellano CP, White MG, Andrews MC, Chelvanambi M, Witt RG, Daniele JR, Titus M, McQuade JL, Conforti F, Burton EM, Lastrapes MJ, Ologun G, Cogdill AP, Morad G, Prieto P, Lazar AJ, Chu Y, Han G, Khan MAW, Helmink B, Davies MA, Amaria RN, Kovacs JJ, Woodman SE, Patel S, Hwu P, Peoples M, Lee JE, Cooper ZA, Zhu H, Gao G, Banerjee H, Lau M, Gershenwald JE, Lucci A, Keung EZ, Ross MI, Pala L, Pagan E, Segura RL, Liu Q, Borthwick MS, Lau E, Yates MS, Westin SN, Wani K, Tetzlaff MT, Haydu LE, Mahendra M, Ma X, Logothetis C, Kulstad Z, Johnson S, Hudgens CW, Feng N, Federico L, Long GV, Futreal PA, Arur S, Tawbi HA, Moran AE, Wang L, Heffernan TP, Marszalek JR, Wargo JA. Nature 606: 2022 797-803	40

Publications

Citations

Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.
Vellano CP, White MG, Andrews MC, Chelvanambi M, Witt RG, Daniele JR, Titus M, McQuade JL, Conforti F, Burton EM, Lastrapes MJ, Ologun G, Cogdill AP, Morad G, Prieto P, Lazar AJ, Chu Y, Han G, Khan MAW, Helmink B, Davies MA, Amaria RN, Kovacs JJ, Woodman SE, Patel S, Hwu P, Peoples M, Lee JE, Cooper ZA, Zhu H, Gao G, Banerjee H, Lau M, Gershenwald JE, Lucci A, Keung EZ, Ross MI, Pala L, Pagan E, Segura RL, Liu Q, Borthwick MS, Lau E, Yates MS, Westin SN, Wani K, Tetzlaff MT, Haydu LE, Mahendra M, Ma X, Logothetis C, Kulstad Z, Johnson S, Hudgens CW, Feng N, Federico L, Long GV, Futreal PA, Arur S, Tawbi HA, Moran AE, Wang L, Heffernan TP, Marszalek JR, Wargo JA. Nature 606: 2022 797-803