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A framework for understanding and targeting residual disease in oncogene-driven solid cancers

Abstract

Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.

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Figure 1: Defining residual disease.

Kim Caesar/Nature Publishing Group

Figure 2: Therapeutic strategies to combat residual disease73.

Kim Caesar/Nature Publishing Group

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Acknowledgements

T.G.B. acknowledges funding support from the US National Institutes of Health Director's Office and Common Fund (New Innovators Award DP2-CA174497), the National Cancer Institute (R01-CA169338), the HHMI Collaborative Innovation Award Program, the Searle Scholars Program, the Pew Charitable Trust, and the Addario Lung Cancer Foundation. R.C.D. acknowledges funding support from the V Foundation for Cancer Research and the University of Colorado Lung Cancer SPORE.

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Correspondence to Trever G Bivona.

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T.G.B. has ownership in Driver Group, is a consultant to Driver Group, Novartis, Astellas, Natera, Array Biopharma, and Ariad, and is a recipient of research grants from Servier and Ignyta. R.C.D. is a consultant to Array BioPharma and Ariad, and has received honoraria from AstraZeneca, Clovis, and Pfizer, research grants from Loxo Oncology, Mirati Therapeutics, and Abbott Molecular, and licensing fees from Chugai, Ariad, Blueprint Medicines, GVKbio, and Abbott Molecular.

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Bivona, T., Doebele, R. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med 22, 472–478 (2016). https://doi.org/10.1038/nm.4091

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