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Adamopoulos C, Ahmed TA, Tucker MR, et al. Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling. Cancer Discov. 2021;11(7):1716-1735doi: 10.1158/2159-8290.CD-20-1351.
Adamopoulos, C., Ahmed, T. A., Tucker, M. R., Ung, P. M. U., Xiao, M., Karoulia, Z., Amabile, A., Wu, X., Aaronson, S. A., Ang, C., Rebecca, V. W., Brown, B. D., Schlessinger, A., Herlyn, M., Wang, Q., Shaw, D. E., & Poulikakos, P. I. (2021). Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling. Cancer discovery, 11(7), 1716-1735. https://doi.org/10.1158/2159-8290.CD-20-1351
Adamopoulos, Christos, et al. "Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling." Cancer discovery vol. 11,7 (2021): 1716-1735. doi: https://doi.org/10.1158/2159-8290.CD-20-1351
Adamopoulos C, Ahmed TA, Tucker MR, Ung PMU, Xiao M, Karoulia Z, Amabile A, Wu X, Aaronson SA, Ang C, Rebecca VW, Brown BD, Schlessinger A, Herlyn M, Wang Q, Shaw DE, Poulikakos PI. Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling. Cancer Discov. 2021 Jul;11(7):1716-1735. doi: 10.1158/2159-8290.CD-20-1351. Epub 2021 Feb 10. PMID: 33568355; PMCID: PMC8295204.
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Cancer Discov. 2021 Jul;11(7):1716-1735. doi: 10.1158/2159-8290.CD-20-1351. Epub 2021 Feb 10.

Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling.

Cancer discovery

Christos Adamopoulos, Tamer A Ahmed, Maxwell R Tucker, Peter M U Ung, Min Xiao, Zoi Karoulia, Angelo Amabile, Xuewei Wu, Stuart A Aaronson, Celina Ang, Vito W Rebecca, Brian D Brown, Avner Schlessinger, Meenhard Herlyn, Qi Wang, David E Shaw, Poulikos I Poulikakos

Affiliations

  1. Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  2. D. E. Shaw Research, New York, New York.
  3. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  4. The Wistar Institute, Philadelphia, Pennsylvania.
  5. Department of Genetics and Genomics Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  6. Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  7. D. E. Shaw Research, New York, New York. [email protected] [email protected].
  8. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York.
  9. Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. [email protected] [email protected].

PMID: 33568355 PMCID: PMC8295204 DOI: 10.1158/2159-8290.CD-20-1351

Abstract

Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF) but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAF

©2021 American Association for Cancer Research.

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