MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines

Abstract

Elevated activity of the MAPK signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival, and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of approximately 20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/STAT3 signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK, and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC, or STAT3 to counteract STAT3-mediated resistance phenotypes.

Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition

“…Compound specificity and cytotoxicity are the most common effects studied, and are critical to drug efficacy and success; however, we argue the potential importance of studying proteolytic activity as a result of drug treatment and propose a simple method with which to study it. Although increased invasion has been observed previously with MEK inhibition and PLX4032 (25,26), we note increased MMP activity as a potential cause of this enhanced motility and consequent displacement. Additionally, in the presence of the general MMP inhibitor GM 6001, no changes were observed in cell migration with or without PLX4032 (Fig.…”

“…Previous reports have observed increased invasion of wild-type BRAF melanoma cells via transwell migration, however in 3D matrices, melanoma cells with mutated V600E BRAF were observed to have increased invasion (25,26). Perhaps the addition of a 3D environment causes differential responses between wildtype and mutated BRAF melanoma cells to inhibitor treatment.…”

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

“…113,114 In addition, the treatment of oncogene-addicted tumor cells treated with EGFR or MEK inhibitors activate STAT3 as a compensatory response, which can induce drug resistance. 115 We postulate that STAT3 activation by these additional means may also be able to drive mesenchymal/CSC properties via interconnection with TGF-b effector signaling. With regard to cancer therapies, suppression of STAT3 in combination with the targeted kinase inhibitors or chemotherapy could prevent the acquisition of more aggressive mesenchymal/CSC properties, and may therefore be a valuable addition to future therapeutic regimes.…”

Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review)

“…Indeed, Stat3 is activated by phosphorylation in melanoma cells that acquired an invasive phenotype following treatment with U0126 or with the BRAF-inhibitor SB590885, and Stat3 knockdown or its inhibition with CPA-7 prevented the appearance of an invasive phenotype and increased cell death in the presence of U0126 or SB590885 (103). …”