We present a cohort of 41 patients with osimertinib resistance biopsies,
including two with an acquired CCDC6-RET fusion. While
RET fusions have been identified in resistant
EGFR-mutant NSCLC, their role in acquired resistance to
EGFR inhibitors is not well described. To assess the biological implications of
RET fusions in an EGFR-mutant cancer, we
expressed CCDC6-RET in PC9 (EGFR del19) and MGH134
(EGFR L858R/T790M) cells and found that CCDC6-RET was
sufficient to confer resistance to EGFR-TKIs. The selective RET inhibitors
BLU-667 or cabozantinib resensitized CCDC6-RET-expressing cells to EGFR
inhibition. Finally, we treated two patients with EGFR-mutant
NSCLC and RET-mediated resistance with osimertinib and BLU-667.
The combination was well-tolerated and led to rapid radiographic response in
both patients. This study provides proof-of-concept that RET
fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and
RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective
treatment strategy for such patients.
The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. , BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants., BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting. Patients with -driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with -altered tumors, clinically validating selective RET targeting..
Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.
Regulation of the hematopoietic transcription factor PU.1 (Spi-1) plays a critical role in the development of white cells, and abnormal expression of PU.1 can lead to leukemia. We previously reported that the PU.1 promoter cannot induce expression of a reporter gene in vivo, and cell-type-specific expression of PU.1 in stable lines was conferred by a 3.4-kb DNA fragment including a DNase I hypersensitive site located 14 kb upstream of the transcription start site. Here we demonstrate that this kb ؊14 site confers lineage-specific reporter gene expression in vivo. This kb ؊14 upstream regulatory element contains two 300-bp regions which are highly conserved in five mammalian species. In Friend virus-induced erythroleukemia, the spleen focus-forming virus integrates into the PU.1 locus between these two conserved regions. DNA binding experiments demonstrated that PU.1 itself and Elf-1 bind to a highly conserved site within the proximal homologous region in vivo. A mutation of this site abolishing binding of PU.1 and Elf-1 led to a marked decrease in the ability of this upstream element to direct activity of reporter gene in myelomonocytic cell lines. These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU
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