Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW (NCT03037385, ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion–positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35–77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib’s potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion–positive solid tumors.
Growth plate abnormalities, associated with impaired hypertrophic chondrocyte apoptosis, are observed in humans and animals with abnormalities of vitamin D action and renal phosphate reabsorption. Low circulating phosphate levels impair hypertrophic chondrocyte apoptosis, whereas treatment of these cells with phosphate activates the mitochondrial apoptotic pathway. Because phosphate-mediated apoptosis of chondrocytes is differentiation-dependent, studies were performed to identify factors that contribute to hypertrophic chondrocyte apoptosis. An increase in the percentage of cells with low mitochondrial membrane potential, evaluated by JC-1 fluorescence, was observed during hypertrophic differentiation of primary murine chondrocytes in culture. This percentage was further increased by treatment of hypertrophic, but not proliferative, chondrocytes with phosphate. Phosphate-mediated apoptosis was observed as early as 30 min post-treatment and was dependent upon Erk1/2 phosphorylation. Inhibition of Erk1/2 phosphorylation in vivo confirmed an important role for this signaling pathway in regulating hypertrophic chondrocyte apoptosis in growing mice. Murine embryonic metatarsals cultured under phosphate-restricted conditions demonstrated a 2.5-fold increase in parathyroid hormone-related protein mRNA expression accompanied by a marked attenuation in phospho-Erk immunoreactivity in hypertrophic chondrocytes. Thus, these investigations point to an important role for phosphate in regulating mitochondrial membrane potential in hypertrophic chondrocytes and growth plate maturation by the parathyroid hormone-related protein signaling pathway.Maturation of the growth of long bones is dependent upon the differentiation of proliferative chondrocytes into prehypertrophic and subsequently hypertrophic chondrocytes. Terminal differentiation of hypertrophic chondrocytes is characterized by the expression of signaling molecules that promote vascular invasion, apoptosis, and replacement of hypertrophic chondrocytes by osteoblasts that lay down the primary spongiosa of bone. Aberrant regulation of this developmental process results in growth plate disorders. Although calcium has been shown to play an important role in regulating chondrocyte maturation (1), apoptosis of terminally differentiated hypertrophic chondrocytes is dependent upon normal levels of circulating phosphate (2).Rickets is a growth plate anomaly observed in growing animals and humans with abnormalities of vitamin D action and renal phosphate reabsorption (3-6). In vivo investigations in genetically modified and dietary-manipulated mouse models demonstrate that hypophosphatemia is the underlying metabolic abnormality that impairs growth plate maturation in these disorders: low circulating phosphate levels result in impaired apoptosis of terminally differentiated hypertrophic chondrocytes in the growth plate, leading to rickets (2). The observation that inhibition of phosphate transport prevents phosphate-mediated apoptosis in hypertrophic chondrocytes (7-9) further ...
While epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors
(TKIs) have changed the treatment landscape for EGFR mutant (L858R
and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients
will eventually develop resistance to TKIs. In the case of first-
and second-generation TKIs, up to 60% of patients will develop an
EGFR T790M mutation, while third-generation irreversible TKIs, like
osimertinib, lead to C797S as the primary on-target resistance mutation.
The development of reversible inhibitors of these resistance mutants
is often hampered by poor selectivity against wild-type EGFR, resulting
in potentially dose-limiting toxicities and a sub-optimal profile
for use in combinations. BLU-945 (compound
30
) is a potent,
reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S
resistance mutants that maintains activity against the sensitizing
mutations, especially L858R. Pre-clinical efficacy and safety studies
supported progression of BLU-945 into clinical studies, and it is
currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven
NSCLC.
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