Clin Cancer Res: Antimalarial drug chloroquine increases the sensitivity of GNAQ/11 mutant melanoma to MEK1/2 inhibitors!

GNAQ or GNA11 (GNAQ/11) activates mutations, seen in more than 90% of patients with vine melanoma, which can lead to carcinogenic pathway composition activation, including MAP kinase and YAP.
so far, chemotherapy or path-targeted therapy, single-use or combination drugs, have been shown to be ineffective in patients with metastasis of vine melanoma.
This study aims to evaluate the role of chloroquine (lysosome inhibitors, antimalarial drugs) or hydroxychloroquine combined MAP kinase pathps to inhibit the effects of GNAQ/11 mutant cells in and outside the body, and to clarify the mechanism of action of MEK1/2 inhibitors combined with chloroquine induced cytotoxicity.
study found that the activation of MAP kinase signals inhibiting GNAQ/11 mediated can induce autophagy.
combined inhibition of G alpha and autophagy or lysosome function can enhance cell death.
addition, the use of quercamine and chloroquine combined inhibition MEK1/2 inhibition and lysosomes can also enhance cytotoxicity.
mice with GNAQ/11-driven melanoma were treated with qumentinib hydroxychloroquine, which inhibited tumor growth and significantly prolonged survival in mice.
is also interesting that the inhibition of lysosomes and autophagy combined quercetinil with baflomycin A1 is not effective in promoting cytotoxicity.
added to the cytoquine combined baflomycin A1, the addition of YAP inhibition can lead to cell death levels comparable to those of quercininib combined chloroquine (T/CQ).
, cells treated with T/CQ showed reduced YAP nuclear positioning and reduced YAP transcription activity.
, which is activated by component expression, can make cancer cells resistant to T/CQ-induced cell death.
In summary, the results of this study show that YAP, MEK1/2, and lysosome functions are essential for GNAQ/11-driven melanoma and can be a key target for the treatment of such melanomas;
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