SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells - PubMed (original) (raw)

SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells

Benoit Pasquier. Autophagy. 2015.

Abstract

Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

Keywords: MTOR; PIK3C3/Vps34; autophagy; renal cell carcinoma; vesicle trafficking.

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Figures

Figure 1.

Figure 1.

(A) Signaling pathways that regulate autophagy. In fed conditions, insulin (INS) and/or growth factors, MTOR complex 1 (MTORC1) is activated via a known signaling pathway including class I PI3K and negatively regulates downstream kinases such as PIK3C3 and ULK1 (unc-51 like autophagy activating kinase 1) leading to a prevention of autophagy. In this condition, MTORC1 is also a key regulator of cell growth. Under starvation, the activity of MTORC1 is suppressed releasing the inhibition of PIK3C3 and ULK1 and allowing the induction of the autophagy machinery. (B) Cellular functions of PIK3C3. The process of autophagy starts with the generation of autophagosomes that then fuse with the lysosome allowing the degradation of the autophagosome contents. Our results using SAR405 demonstrated that PIK3C3 has a dual role during the initial steps of autophagy, with the generation of autophagosomes, and also during endocytosis between late endosomes to lysosomes.

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