TY - JOUR
T1 - State-of-the-art strategies for targeting RET-dependent cancers
AU - Subbiah, Vivek
AU - Yang, Dong
AU - Velcheti, Vamsidhar
AU - Drilon, Alexander
AU - Meric-Bernstam, Funda
N1 - Funding Information:
Supported in part by Cancer Prevention and Research Institute of Texas Grant No. RP1100584; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Grant No. 1U01 CA180964; National Center for Advancing Translational Sciences Grant No. UL1 TR000371; and MD Anderson Cancer Center Support Grant No. P30 CA016672.
Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2020/4/10
Y1 - 2020/4/10
N2 - Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non–small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
AB - Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non–small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
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U2 - 10.1200/JCO.19.02551
DO - 10.1200/JCO.19.02551
M3 - Article
C2 - 32083997
AN - SCOPUS:85083003525
SN - 0732-183X
VL - 38
SP - 1209
EP - 1221
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 11
ER -