Cancer discovery
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In a phase I trial of endoxifen, a metabolite of tamoxifen, multiple patients with estrogen receptor-positive breast cancer that was resistant to treatment with aromatase inhibitors had partial responses or long-lasting stable disease.
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The U. S. Food and Drug Administration (FDA) has approved the targeted therapy ibrutinib (Imbruvica; Johnson & Johnson and Pharmacyclics) for treating patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
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Mutations that activate the small GTP-binding protein KRAS are the most common oncogenic event in human tumors. Thirty years after its discovery, mutant KRAS has yet to be therapeutically conquered.
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Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. ⋯ MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
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Because of concerns about serious cardiovascular side effects, the U. S. Food and Drug Administration asked Ariad Pharmaceuticals to temporarily suspend sales and marketing of ponatinib to treat chronic myeloid leukemia in patients resistant to first-line therapy.