Synergistic targeting of the PI3K/mTOR and MAPK/ERK pathways in Merkel cell carcinoma

ElsevierVolume 14, December 2022, 200244Tumour Virus ResearchAbstract

Merkel cell carcinoma (MCC) is an aggressive type of skin cancer, which is caused either by integration of the oncogenic Merkel cell polyomavirus (MCPyV) or by accumulation of UV-light induced mutations. Since the response to immune-checkpoint inhibitors is limited, new therapeutic agents need to be explored. Previous studies have shown that MCC cell lines and xenografts are sensitive to MLN0128, a dual mTOR1/2 inhibitor. Prompted by these results and considering that the PI3K/mTOR and MAPK/ERK pathways are the most commonly deregulated pathways in cancer, the combination of MLN0128 with the MEK1/2 inhibitor trametinib was investigated. Importantly, the combined targeting showed to be synergistic in MCC cell lines and induced alterations in the protein levels of downstream elements of the targeted pathways. This synergistic activity implies a reduction in the dose of each inhibitor necessary to reach the same effect that when used as single agents. Therefore, this is a promising approach to improve the clinical management of MCC and to overcome the limited efficacy of single drug regimens owed to the appearance of toxicity or drug resistance.

Keywords

Merkel cell carcinoma

Merkel cell polyomavirus

Synergism

Combined targeting

Pathway inhibition

AbbreviationsMCPyV+

Merkel cell polyomavirus-positive;

MCPyV-

Merkel cell polyomavirus-negative;

MCC

Merkel cell carcinoma;

PI3K/mTOR)

phosphatidylinositol 3-kinase/mammalian target of rapamycin;

FDA

Food and Drug Administration;

MAPK/ERK

mitogen-activated protein kinase/extracellular-signal-regulated kinase;

mTORC1/2

mammalian target of rapamycin complex 1/2 or mechanistic target of rapamycin complex 1/2;

© 2022 Published by Elsevier B.V.

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