WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

Abstract

About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF V600E/K ) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFiresistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.

Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy

“…Indeed, high expression of Wnt5a, a marker of the invasive phenotype, was found to induce resistance to BRAF inhibitors in patients (14). In vitro-acquired data show the same trendthe invasive phenotype can be linked to both intrinsic and acquired resistance to BRAF or MEK inhibitors (13,15).…”

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

“…We also evaluated our CTL PLX4720 and BMI PLX4720 populations for the expression of DE genes that are up-regulated by BMI1 and known to be key determinants for BRAFi resistance in melanoma, such as EGFR, PDGFR, and Wnt5a Anastas et al 2014;Sabbatino et al 2014;Sun et al 2014). We found that Wnt5a was further up-regulated in all of the BMI PLX4720 populations, compared with vehicle-treated BMI1 controls, and was also specifically induced in the CTL PLX4720 line that had up-regulated its endogenous BMI1 (Fig.…”

WNT5A and Its Receptors in the Bone-Cancer Dialogue

“…In this context WNT5A was increased in BRAF inhibitor-resistant cell lines and in patient tumors, leading to a promotion of melanoma growth. (66,67) Another study dealing with changes in energy metabolism found WNT5A to increase the aggressive behavior of melanoma cells beyond the enhancement of aerobic glycolysis. (68) In contrast, downregulation of WNT5A showed inhibitory effects on melanoma cell invasion.…”

“…Yes (137)(138)(139) Yes (140) Breast cancer (89) ; melanoma (66) ; ovarian cancer (141) 38,40) ). Inhibition of FZD5 resulted in inhibited proliferation and migration (2 (75) ).…”

“…(92) Thus O'Connell and colleagues (90) suggested that WNT5A and ROR2 synergistically increased the metastatic potential in melanoma. Melanoma tumor progression under BRAF inhibitor (BRAFi) treatment has been found to depend on increased WNT5A expression leading to Akt signaling activation through FZD7 and RYK (66) (Fig. 2C, label 2).…”