TY - JOUR
T1 - BRAF targeting sensitizes resistant melanoma to cytotoxic T cells
AU - Atay, Cigdem
AU - Kwak, Taekyoung
AU - Lavilla-Alonso, Sergio
AU - Donthireddy, Laxminarasimha
AU - Richards, Allison
AU - Moberg, Valerie
AU - Pilon-Thomas, Shari
AU - Schell, Michael
AU - Messina, Jane L.
AU - Rebecca, Vito W.
AU - Xiao, Min
AU - Tan, Jiufeng
AU - Zhang, Gao
AU - Weber, Jeffrey S.
AU - Herlyn, Meenhard
AU - Sarnaik, Amod A.
AU - Gabrilovich, Dmitry I.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Purpose: BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi. Experimental Design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT. Results: Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment. Conclusions: BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.
AB - Purpose: BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi. Experimental Design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT. Results: Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment. Conclusions: BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.
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U2 - 10.1158/1078-0432.CCR-18-2725
DO - 10.1158/1078-0432.CCR-18-2725
M3 - Article
C2 - 30765391
AN - SCOPUS:85065508739
SN - 1078-0432
VL - 25
SP - 2783
EP - 2794
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -