Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2–4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.

Vellano, C., White, M., Andrews, M., Chelvanambi, M., Witt, R., Daniele, J., et al. (2022). Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy. NATURE, 606(7915), 797-803 [10.1038/s41586-022-04833-8].

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

Pagan, Eleonora;
2022

Abstract

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2–4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.
Articolo in rivista - Articolo scientifico
Scientifica
BRAF/MEK targeted therapy; Melanoma; neoadjuvant treatment; Androgen receptor;
English
Vellano, C., White, M., Andrews, M., Chelvanambi, M., Witt, R., Daniele, J., et al. (2022). Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy. NATURE, 606(7915), 797-803 [10.1038/s41586-022-04833-8].
Vellano, C; White, M; Andrews, M; Chelvanambi, M; Witt, R; Daniele, J; Titus, M; Mcquade, J; Conforti, F; Burton, E; Lastrapes, M; Ologun, G; Cogdill, A; Morad, G; Prieto, P; Lazar, A; Chu, Y; Han, G; Khan, M; Helmink, B; Davies, M; Amaria, R; Kovacs, J; Woodman, S; Patel, S; Hwu, P; Peoples, M; Lee, J; Cooper, Z; Zhu, H; Gao, G; Banerjee, H; Lau, M; Gershenwald, J; Lucci, A; Keung, E; Ross, M; Pala, L; Pagan, E; Segura, R; Liu, Q; Borthwick, M; Lau, E; Yates, M; Westin, S; Wani, K; Tetzlaff, M; Haydu, L; Mahendra, M; Ma, X; Logothetis, C; Kulstad, Z; Johnson, S; Hudgens, C; Feng, N; Federico, L; Long, G; Futreal, P; Arur, S; Tawbi, H; Moran, A; Wang, L; Heffernan, T; Marszalek, J; Wargo, J
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/383814
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