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Resistance to PI3K Pathway Inhibition

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PI3K-mTOR in Cancer and Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancer and aberrant activation promotes transformation. Major efforts are currently being aimed at pharmacologically targeting the pathway for cancer therapy. Early results have yielded more limited success than has been seen for other selective inhibitors of mutant oncoprotein drivers. In this chapter, we review the biological reasons that may account for such intrinsic and acquired resistance to PI3K-targeted therapy. Mechanisms of resistance commonly seen in models include: (1) relief of negative feedback regulatory programs resulting in induction of upstream pathway signaling, which counteracts drug action and attenuates efficacy and (2) coincident activation of alternate growth signaling pathways. The understanding of how tumors with oncogenic PI3K pathway activation circumvent pharmacologic inhibition suggests that combination therapy will be necessary in many contexts in order to see durable responses. Indeed, more recent clinical efforts testing PI3K-directed therapy have been designed under the assumption that up front combination therapy will be necessary for efficacy. These clinical trials are increasingly employing state-of-the-art correlative analyses including next generation sequencing to determine predictors of sensitivity. Clinical data paired with these correlative analyses will be indispensible in determining the optimal agents, combinations, and genotypes to treat.

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Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Payal D. Shah

  2. Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Sarat Chandarlapaty

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  1. Payal D. Shah
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Correspondence to Sarat Chandarlapaty .

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Editors and Affiliations

  1. Oncology, Head of Cancer Biology, Avera Cancer Instit Center for Precision, SIOUX FALLS, South Dakota, USA

    Nandini Dey

  2. Oncology, Head of Translational Oncology, Avera Cancer Institute Center for Preci, Sioux Falls, South Dakota, USA

    Pradip De

  3. Precision Oncology,, Avera Cancer Institute Center for, Sioux Falls, South Dakota, USA

    Brian Leyland-Jones

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Shah, P.D., Chandarlapaty, S. (2016). Resistance to PI3K Pathway Inhibition. In: Dey, N., De, P., Leyland-Jones, B. (eds) PI3K-mTOR in Cancer and Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-34211-5_5

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  • DOI: https://doi.org/10.1007/978-3-319-34211-5_5

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