Targeting STAT3 restores BRAF inhibitor sensitivity through miR-759-3p in human cutaneous melanoma cells.

Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits, but the common emergence of drug resistance remains a challenge. To define molecular mechanisms of vemurafenib resistance, we generated A375-R, WM35-R cell lines resistant to vemurafenib and found that the p-STAT3 was upregulated in these cells in vitro and in vivo. In particular, activation of the STAT3 pathway was associated with vemurafenib resistance. Inhibition of this pathway with STAT3-specific siRNA (shRNA) sensitized A375-R, WM35-R cells to vemurafenib and induced apoptosis in vitro and in vivo. Moreover, targeting STAT3 induced expression of miR-579-3p and elicited resistance to vemurafenib. However, targeting miR-579-3p with anti- miR-579-3p reversed the resistance to vemurafenib. Together, these results indicate that STAT3-mediated downexpression of miR-579-3p caused resistance to vemurafenib. Our findings suggest novel approaches to overcome resistance to vemurafenib by combining vemurafenib with STAT3 silencing or miR-579-3p overexpression.

Su Y ，Yu Y ，He D ，Zhang J ，Wang Z ，Sun P ，Chen Z ... -  《International Journal of Clinical and Experimental Pathology》

Targeting signal-transducer-and-activator-of-transcription 3 sensitizes human cutaneous melanoma cells to BRAF inhibitor.

Wang X ，Qu H ，Dong Y ，Wang G ，Zhen Y ，Zhang L ... -  《-》

Signal transducer and activator of transcription 3 inhibition enhances vemurafenib sensitivity in colon cancers harboring the BRAF(V600E) mutation.

The BRAFV600E inhibitor vemurafenib is widely used to treat melanomas harboring the activated BRAFV600E mutation; however, vemurafenib showed poor efficacy in colon cancer, which impeded its clinical application for colon cancer patients with this mutation. The specific mechanism of vemurafenib resistance is not clear in colon cancer. In this study, we demonstrated that signal transducer and activator of transcription 3 (STAT3) activation influenced vemurafenib sensitivity in BRAFV600E mutant colon cancer cells. When vemurafenib was applied to two colon cancer cell lines with the BRAFV600E mutation, STAT3 was continuously activated after 6 hours. Furthermore, BCL-2 was upregulated in RKO colon cancer cells, while STAT3 remained unchanged in HT-29 colon cancer cells. This suggested that STAT3 signaling might be involved in vemurafenib sensitivity. Combining the STAT3 inhibitor STATTIC with vemurafenib further inhibited cell proliferation and promoted apoptosis by downregulating STAT3 and BCL-2 expression in RKO cells. Further studies showed that interleukin 6 (IL-6) secretion increased after RKO cells were treated with vemurafenib. STAT3 activation was induced by adding IL-6 to the supernatant, and IL-6 increased STAT3 and BCL-2 expression and antagonized vemurafenib sensitivity in HT-29 cells. Together, these results suggest that STAT3 activation maybe related to vemurafenib sensitivity in colon cancer cells, and that combining STAT3 inhibitors with vemurafenib may be a promising treatment for BRAFV600E mutant colon cancers.

Wang K ，Li Y ，Song N ，Che X ，Hou K ，Xu L ，Bai M ，Wang Q ，Wang Y ，Zhou Y ，Cao M ，Liu Y ，Zhang J ... -  《-》

miR-410-3p is induced by vemurafenib via ER stress and contributes to resistance to BRAF inhibitor in melanoma.

Grzywa TM ，Klicka K ，Paskal W ，Dudkiewicz J ，Wejman J ，Pyzlak M ，Włodarski PK ... -  《PLoS One》

miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma.

Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naïve human melanoma cells was sufficient to confer vemurafenib resistance and more robust tumor growth in vivo Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after vemurafenib exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses.Significance: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Cancer Res; 78(4); 1017-30. ©2017 AACR.

Díaz-Martínez M ，Benito-Jardón L ，Alonso L ，Koetz-Ploch L ，Hernando E ，Teixidó J ... -  《-》