T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells

Karol Granados,Lionel Larribère,Daniel Novak,Jochen Utikal,Viktor Umansky,Laura Hüser,Aniello Federico,Marlene Vierthaler,Qian Sun,Verónica Madrigal-Gamboa,Thomas Hielscher,Gretchen Wolff,Sachindra Sachindra

doi:10.1038/s41416-020-0751-8

Abstract

BackgroundDrug resistance remains as one of the major challenges in melanoma therapy. It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi).MethodsWe investigated the melanoma phenotype switching using a partial reprogramming model to de-differentiate murine melanoma cells and target melanoma therapy adaptation against MAPKi.ResultsHere, we show that partially reprogrammed cells are a less proliferative and more de-differentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate adaptation to MAPKi, cells were exposed to B-Raf Proto-Oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. De-differentiated cells became less sensitive to MAPKi, showed increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels expression increased in adaptive murine cells and in human adaptive melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo.ConclusionIn summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.

Highlights

Drug resistance remains as one of the major challenges in melanoma therapy
Here, we have demonstrated that partial reprogramming of melanoma cells induced a de-differentiated phenotype and increased adaptation against mitogen-activated protein kinase inhibitors (MAPKi)
We observed that T-type calcium channels expression increased in MAPKi-adaptive melanoma cells and that inhibition of T-type calcium channels enhanced cell death and differentiation in reprogrammed melanoma cells and in human BRAFi-adaptive melanoma cells

Summary

Introduction

It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). CONCLUSION: In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells. The clinical use of BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (trametinib, cobimetinib, binimetinib) or their combinations significantly increase progression-free and overall survival of patients.[3,4] most patients develop resistance to these inhibitors soon after the start of therapy[5,6] because of different factors including tumour heterogeneity and plasticity.[7]. Melanoma cells switch between proliferative/differentiated and invasive/de-differentiated phenotypes during metastasis progression, mimicking the epithelial-to-mesenchymal transition, which facilitates invasion to secondary tumour sites.[8,9,10] induction of phenotype switching towards a de-differentiated state is likely one of the most common mechanisms underlying the development of resistance to therapies in melanoma patients.[9]

Methods

Results

Conclusion