SummarySorting from the Golgi apparatus requires the recruitment of cytosolic coat proteins to package cargo into trafficking vesicles. An important early step in the formation of trafficking vesicles is the activation of Arf1 by the guanine nucleotide exchange factor GBF1. To activate Arf1, GBF1 must be recruited to and bound to Golgi membranes, a process that requires Rab1b. However, the mechanistic details of how Rab1 is implicated in GBF1 recruitment are not known. In this study, we demonstrate that the recruitment of GBF1 also requires phosphatidylinositol 4-phosphate [PtdIns(4)P]. Inhibitors of PtdIns(4)P synthesis or depletion of PI4KIII, a phosphatidylinositol 4-kinase localized to the endoplasmic reticulum and Golgi, prevents the recruitment of GBF1 to Golgi membranes. Interestingly, transfection of dominant-active Rab1 increased the amount of PtdIns(4)P at the Golgi, as detected by GFP-PH, a PtdIns(4)P-sensing probe. We propose that Rab1 contributes to the specificity and timing of GBF1 recruitment by activating PI4KIII. The PtdIns(4)P produced then allows GBF1 to bind to Golgi membranes and activate Arf1.

The addition of CDK 4/6 inhibitors (either abemaciclib, palbociclib, or ribociclib) to an AI (anastrozole or letrozole) significantly improved PFS, overall response rate, and clinical benefit rate in comparison with a nonsteroidal AI alone.

Although not considered curative in nature, new therapeutic advances in metastatic breast cancer (MBC) have substantially improved patient outcomes. This article discusses the state-of-the-art and emerging therapeutic options for management of MBC. BC systemic therapy targets multiple key pathways, including estrogen receptor signaling, HER2 signaling, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Other therapeutic strategies include targeting DNA repair, inhibiting immune checkpoints, and developing antibody-drug conjugates. Although surgery historically was reserved for palliation of symptomatic, large, or ulcerating masses, some data suggest a possibly expanding role for more aggressive locoregional therapy in combination with systemic therapy. As technology develops, biomarker-specific, line-agnostic, and receptor-agnostic treatment strategies will redraw the current lines of MBC care. However, tumor heterogeneity remains a challenge. To effectively reshape our approach to MBC, careful consideration of the patient perspective, the costs and value of novel treatments, and accessibility (especially in developing countries) is paramount.

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