Clin Cancer Res: Targeting extracellular substate reconstruction restores BRAFi-resistant melanoma's sensitivity to BRAF inhibitors.

Extracellular substations (ECMs) are involved in the treatment of drug resistance, but their specific role in the production of resistance is not yet clear.
in this study, Marusak and others studied the role of ECM reconstruction in braf mutation melanoma resistance to BRAF inhibitor therapy through collagenase MT1-MMP.
used public RNA sequencing (RNAseq) data and inverse protein arrays (RPPa) to determine the correlation between MT1-MMP and BRAFi-resistant melanoma patients, PDX, and cell-line-origin tumors.
MT1-MMP is removed by shRNA mediated, MT1-MMP is inhibited by selective MT1-MMP/MMP2 inhibitor ND322, or MT1-MMP is over-expressed to assess the role of MT1-MMP in mediated resistance to BRAFi.
MT1-MMP continued to increase in tumor samples, melanoma allogeneic transplants, and brafi-resistant cell linelines from patients with progression.
MT1-MMP inhibition, mediated by shRNA or ND322, in collaboration with BRAFi can lead to resensitivity of drug-resistant cells and tumors to BRAFi.
depends on the ability of cells to divide ECM.
cells inoculated in the non-dividable substation MT1-MMP re-sensitive to BRAFi, similar to MT1-MMP inhibition.
this is because cells cannot activate the integrator beta 1/FAK signal in the case of MT1-MMP inhibition, because the activity of the recovery of the integrator beta 1 is sufficient to maintain resistance to BRAFi.
, in BRAF-resistant cells, the increase in MT1-MMP depends on TGF beta, as inhibiting TGFb subject I/II limits the over-expression of MT1-MMP and restores the sensitivity of tumor cells to BRAF inhibition.
, BRAF inhibition causes pressure in tumor cells by selectively high expression of MT1-MMP.
MT1-MMP play a key role in the ECM-based signaling pathrapies that lead to resistance to BRAFi therapy.
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