TY - JOUR
T1 - RETooling the RET Inhibitor Pralsetinib for ESR1 Fusion–Positive Breast Cancer and Beyond
AU - Wu, Jie
AU - Subbiah, Vivek
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Transcriptionally active fusions of ESR1 (ESR1-TAF) and somatic mutations in the estrogen receptor alpha (ERa) ligand-binding domain (LBD) cause endocrine therapy resistance in breast cancer. In searching for therapeutic target kinase(s) in these breast cancers, Gou and colleagues identified FLT4, RET, JAK1, and IGF1R as the top upregulated kinases induced by ESR1-TAFs and ERa LBD mutants in breast cancer cells. Among them, inhibition of RET by pralsetinib suppressed ESR1-TAF–driven and ERa LBD mutant– driven cell proliferation and patient-derived xenograft growth. Pralsetinib is an inhibitor of the RET protein tyrosine kinase that is approved for treating oncogenic RET mutation–positive and RET fusion–positive thyroid cancers and non–small cell lung cancer. The work by Gou and colleagues reinforces the knowledge of RET as an ESR1 target gene and highlights that RET interacts with ERa to promote breast cancer tumorigenesis and antiestrogen resistance. It also raises the prospect of repositioning pralsetinib to target wildtype RET in ER-positive breast cancer.
AB - Transcriptionally active fusions of ESR1 (ESR1-TAF) and somatic mutations in the estrogen receptor alpha (ERa) ligand-binding domain (LBD) cause endocrine therapy resistance in breast cancer. In searching for therapeutic target kinase(s) in these breast cancers, Gou and colleagues identified FLT4, RET, JAK1, and IGF1R as the top upregulated kinases induced by ESR1-TAFs and ERa LBD mutants in breast cancer cells. Among them, inhibition of RET by pralsetinib suppressed ESR1-TAF–driven and ERa LBD mutant– driven cell proliferation and patient-derived xenograft growth. Pralsetinib is an inhibitor of the RET protein tyrosine kinase that is approved for treating oncogenic RET mutation–positive and RET fusion–positive thyroid cancers and non–small cell lung cancer. The work by Gou and colleagues reinforces the knowledge of RET as an ESR1 target gene and highlights that RET interacts with ERa to promote breast cancer tumorigenesis and antiestrogen resistance. It also raises the prospect of repositioning pralsetinib to target wildtype RET in ER-positive breast cancer.
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U2 - 10.1158/0008-5472.CAN-23-1021
DO - 10.1158/0008-5472.CAN-23-1021
M3 - Article
C2 - 37779428
AN - SCOPUS:85173130945
SN - 0008-5472
VL - 83
SP - 3159
EP - 3161
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -