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Adaptive stress signaling in targeted cancer therapy resistance

Oncogene volume 34, pages 5599–5606 (2015)Cite this article

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Abstract

The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. Although substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumo r cell survival during treatment and the development of resistance. Here we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize or eliminate targeted therapy resistance, thereby unleashing the full potential of targeted therapies to transform many cancers from lethal to chronic or curable conditions.

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Acknowledgements

We thank members of the Bivona lab for critical review and thoughtful comments on the manuscript. We are grateful to the following funding sources: NIH Director’s New Innovator Award, NIH R01 CA169338, Howard Hughes Medical Institute, Doris Duke Charitable Foundation, Searle Scholars Program, California Institute for Quantitative Biosciences, QB3@UCSF (to TGB).

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  1. Division of Hematology-Oncology, Department of Medicine, San Francisco, CA, USA

    E Pazarentzos & T G Bivona

  2. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    E Pazarentzos & T G Bivona

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Correspondence to T G Bivona.

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TGB is a consultant to Driver Group and to Novartis, Clovis Oncology, Cleave Biosciences, and a recipient of a research grant from Servier. EP declares no conflict of interest.

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Pazarentzos, E., Bivona, T. Adaptive stress signaling in targeted cancer therapy resistance. Oncogene 34, 5599–5606 (2015). https://doi.org/10.1038/onc.2015.26

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