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Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations.
J Med Chem
December 2024
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Rearranged during transfection (RET) kinase is a validated therapeutic target for various cancers characterized by RET alterations. Although two selective RET inhibitors, selpercatinib and pralsetinib, have been approved by the FDA, acquired resistance through solvent-front mutations has been identified rapidly. Developing proteolysis targeting chimera (PROTAC) targeting RET mutations offers a promising strategy to combat drug resistance.
View Article and Find Full Text PDFTargeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.
J Med Chem
December 2024
Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
The rearranged-during-transfection (RET) kinase is a validated target for the treatment of RET-altered cancers. Currently approved RET-selective kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), increase the oncogenic RET protein level upon treatment, which may affect their efficacy. We seek to reduce the oncogenic RET protein level and RET kinase activity simultaneously.
View Article and Find Full Text PDFClinical utility and predictive value of cerebrospinal fluid cell-free DNA profiling in non-small cell lung cancer patients with leptomeningeal metastasis.
Neoplasia
December 2024
Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan.
Leptomeningeal metastasis (LM) is a challenging complication of non-small cell lung cancer (NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using next-generation sequencing (NGS) offers insights into resistance mechanisms and potential treatment strategies. We conducted a study from February 2022 to April 2023 involving patients from five hospitals in Taiwan who had recurrent or advanced NSCLC with LM.
View Article and Find Full Text PDFEvolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC).
BMC Pulm Med
November 2024
Department of Oncology, the First Medical Center of PLA General Hospital, (Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs (Ministry of Education, China)), Beijing, 100853, China.
Article Synopsis
- - The study reviews advancements in research on RET rearrangements in solid tumors, specifically focusing on therapeutic strategies and outcomes in advanced non-small cell lung cancer (NSCLC) within China.
- - It analyzes the incidence of RET rearrangements, treatment approaches, and evaluates the effectiveness of targeted RET inhibitors, particularly assessing real-world patient outcomes.
- - A retrospective analysis of 64 patients shows that the KIF5B-RET fusion is the most common, with Pralsetinib achieving a median progression-free survival of 16.03 months, significantly better than chemotherapy.
MIG6 loss increased RET inhibitor tolerant persister cells in RET-rearranged non-small cell lung cancer.
Cancer Lett
November 2024
Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address:
Article Synopsis
- Recent RET tyrosine kinase inhibitors (TKIs) show promise for treating RET-rearranged non-small cell lung cancer (NSCLC) and RET-mutated thyroid cancer, but resistance limits their effectiveness over time.* -
- A CRISPR/Cas9 screening identified genes related to drug-tolerant persister cells, revealing that loss of MED12 or MIG6 increases these resistant cells and activates EGFR, leading to treatment failure.* -
- Combining EGFR inhibitors with RET TKIs proved effective in overcoming resistance, and further experiments indicated that targeting either EGFR or RET enhances sensitivity to treatments in resistant cancer models.*
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