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Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

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Abstract

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity – imatinib, sunitinib, and regorafenib – are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.

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Authors and Affiliations

  1. Department of Medical Oncology, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, P. Vall d’Hebron 119, 08035, Barcelona, Spain

    César Serrano, Claudia Valverde, Cristina Suárez, Rafael Morales-Barrera & Joan Carles

  2. Sarcoma Translational Research Laboratory, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, P. Vall d’Hebron 119, 08035, Barcelona, Spain

    César Serrano, David Olivares & Alfonso García-Valverde

  3. Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Suzanne George

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Suzanne George

  5. Universitat Internacional de Catalunya, Barcelona, Spain

    Joan Carles

Authors
  1. César Serrano
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  2. Suzanne George
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  3. Claudia Valverde
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  4. David Olivares
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  5. Alfonso García-Valverde
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  6. Cristina Suárez
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  7. Rafael Morales-Barrera
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  8. Joan Carles
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Corresponding author

Correspondence to César Serrano.

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Funding

This work has been supported by a SARC Sarcoma Spore (1U54CA168512–01) and an Instituto de Salud Carlos III PI16/01371 grants (both to César Serrano).

Conflict of Interest

César Serrano has received grants from Deciphera Pharmaceuticals and Bayer Healthcare, and payment for lectures including service on speaker bureaus from Bayer Healthcare. Claudia Valverde has received consulting fees (advisory boards) from Novartis, Pfizer, and Bayer, and payments for educational lectures from Novartis and Bayer. Suzanne George has received grants from Pfizer and Bayer, consulting fees or honorarium from AstraZeneca (pending) and Deciphera (pending), and clinical trial support from Deciphera and Blueprint Medicines. All other authors declare no conflict of interest.

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Serrano, C., George, S., Valverde, C. et al. Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors. Targ Oncol 12, 277–288 (2017). https://doi.org/10.1007/s11523-017-0490-9

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