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Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways

Abstract

Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.

Key points

  • In any particular cell, the expression of a given protein fluctuates dynamically around a pre-set homeostatic level, contributing to temporal heterogeneity. At the cell-population level, the expression of a given protein fits a log-normal distribution, contributing to spatial heterogeneity.

  • Cell state is mostly determined by the expression levels of different proteins, which is a continuous quantitative variable and can be perturbed by extrinsic stress, such as drug exposure.

  • The development of resistance to targeted therapy and immunotherapy can be divided into three phases, namely, early survival (including persister cells and innate resistant cells), reversal of senescence and new homeostasis; along these phases, resistance gradually changes from reversible to irreversible.

  • The persister cell subpopulation is programmed to tolerate cell death and capable of surviving harsh environmental conditions, such as hypoxia, lack of nutrients and exposure to targeted therapy and/or immunotherapy.

  • Future therapeutic developments should take into account the highly dynamic heterogeneity and the existence of distinct homeostatic states of tumour cells.

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Fig. 1: Dynamic fluctuation model.
Fig. 2: MITF expression and phenotype switching in melanoma before and after treatment with targeted agents.
Fig. 3: Reshaping of cell states at different stages in melanoma.
Fig. 4: IFNγ–JAK1/JAK2–STAT1/STAT3 pathway in melanoma.

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Acknowledgements

D.E.F. acknowledges grant support from the NIH (5P01 CA163222 and 2R01 AR043369) and the Dr Miriam and Sheldon G. Adelson Medical Research Foundation. K.T.F. acknowledges grant support from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation.

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All authors made substantial contributions to researching data for the article, discussions of content and writing and reviewing and/or editing of the manuscript before submission.

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D.E.F. has a financial interest associated with Soltego, which was reviewed and is currently managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. K.T.F. serves on the Board of Directors of Clovis Oncology, Loxo Oncology, Strata Oncology and Vivid Biosciences; serves on the Corporate Advisory Boards of PIC Therapeutics and X4 Pharmaceuticals; serves on the Scientific Advisory Boards of Adaptimmune, Aeglea, Amgen, Apricity, Arch Oncology, Array BioPharma, Asana, Fog Pharma, Fount, Neon Therapeutics, Oncoceutics, Sanofi, Shattuck Labs, Tolero and Tvardi; and is a consultant to Bristol-Myers Squibb, Boston Biomedical, Cell Medica, Checkmate, Debiopharm, Genentech, Merck, Novartis, Pierre Fabre, Takeda and Verastem. X.B. declares no competing interests.

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Bai, X., Fisher, D.E. & Flaherty, K.T. Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways. Nat Rev Clin Oncol 16, 549–562 (2019). https://doi.org/10.1038/s41571-019-0204-6

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