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Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.
Vellano, Christopher P; White, Michael G; Andrews, Miles C; Chelvanambi, Manoj; Witt, Russell G; Daniele, Joseph R; Titus, Mark; McQuade, Jennifer L; Conforti, Fabio; Burton, Elizabeth M; Lastrapes, Matthew J; Ologun, Gabriel; Cogdill, Alexandria P; Morad, Golnaz; Prieto, Peter; Lazar, Alexander J; Chu, Yanshuo; Han, Guangchun; Khan, M A Wadud; Helmink, Beth; Davies, Michael A; Amaria, Rodabe N; Kovacs, Jeffrey J; Woodman, Scott E; Patel, Sapna; Hwu, Patrick; Peoples, Michael; Lee, Jeffrey E; Cooper, Zachary A; Zhu, Haifeng; Gao, Guang; Banerjee, Hiya; Lau, Mike; Gershenwald, Jeffrey E; Lucci, Anthony; Keung, Emily Z; Ross, Merrick I; Pala, Laura; Pagan, Eleonora; Segura, Rossana Lazcano; Liu, Qian; Borthwick, Mikayla S; Lau, Eric; Yates, Melinda S; Westin, Shannon N; Wani, Khalida; Tetzlaff, Michael T; Haydu, Lauren E; Mahendra, Mikhila; Ma, XiaoYan.
Afiliación
  • Vellano CP; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • White MG; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Andrews MC; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Chelvanambi M; Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
  • Witt RG; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Daniele JR; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Titus M; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • McQuade JL; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Conforti F; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Burton EM; Division of Melanoma, Sarcomas, and Rare Tumors, European Institute of Oncology, IRCCS, Milan, Italy.
  • Lastrapes MJ; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ologun G; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Cogdill AP; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Morad G; Department of Surgery, Guthrie Courtland Medical Center, Courtland, NY, USA.
  • Prieto P; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lazar AJ; Immunai, New York, NY, USA.
  • Chu Y; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Han G; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Khan MAW; Department of Surgery, University of Rochester, Rochester, NY, USA.
  • Helmink B; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Davies MA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Amaria RN; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Kovacs JJ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Woodman SE; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Patel S; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Hwu P; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Peoples M; Department of Surgery, Washington University in St Louis, St Louis, MO, USA.
  • Lee JE; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Cooper ZA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Zhu H; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Gao G; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Banerjee H; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lau M; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Gershenwald JE; Moffitt Cancer Center, Tampa, FL, USA.
  • Lucci A; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Keung EZ; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ross MI; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Pala L; AstraZeneca, Gaithersburg, MD, USA.
  • Pagan E; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Segura RL; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Liu Q; Clinical Development and Analytics, Novartis Pharmaceuticals, East Hanover, NJ, USA.
  • Borthwick MS; Novartis Pharma, Basel, Switzerland.
  • Lau E; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Yates MS; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Westin SN; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wani K; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Tetzlaff MT; Division of Melanoma, Sarcomas, and Rare Tumors, European Institute of Oncology, IRCCS, Milan, Italy.
  • Haydu LE; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.
  • Mahendra M; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ma X; Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Nature ; 606(7915): 797-803, 2022 06.
Article en En | MEDLINE | ID: mdl-35705814
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Quinasas de Proteína Quinasa Activadas por Mitógenos / Proteínas Proto-Oncogénicas B-raf / Antagonistas de Receptores Androgénicos / Terapia Molecular Dirigida / Melanoma Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Quinasas de Proteína Quinasa Activadas por Mitógenos / Proteínas Proto-Oncogénicas B-raf / Antagonistas de Receptores Androgénicos / Terapia Molecular Dirigida / Melanoma Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido