In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells
- Florencia Paula Madorsky Rowdo
- Antonela Barón
- Erika María von Euw
- José Mordoh
Affiliations: Leloir Institute, IIBBA-CONICET, Buenos Aires, Argentina, Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
- Published online on: January 13, 2017 https://doi.org/10.3892/or.2017.5363
Copyright: © Madorsky Rowdo
et al. This is an open access article distributed under the
terms of Creative
Commons Attribution License.
Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
This article is mentioned in:
The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of long‑term in vitro treatment of two different V600E BRAF‑mutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR). Markedly, discontinuing treatment of SUR cells with MAPK inhibitors allowed the population to regrow and these cells retained drug sensitivity equal to that of the parental cells. SUR cells had increased expression levels of CD271 and ABCB5 and presented senescence-associated characteristics. Notably, SUR cells were efficiently lysed by cytotoxic T lymphocytes recognizing MART-1 and gp100 melanoma differentiation antigens. We propose quiescent plasticity as a mechanism of resistance to BRAF and MEK inhibitors while retaining sensitivity to immune effectors.