Everolimus for the treatment of advanced pancreatic ductal adenocarcinoma (PDAC)

Abstract

Introduction: PDAC is a lethal malignancy with a clear unmet need; almost all patients fail 1^st, 2^nd, and 3^rd line multi-agent cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) has been identified as a key signaling node enhancing tumor survival and drug resistance in PDAC; hence, it is considered a promising therapeutic target. Areas covered: We comprehensively reviewed the evidence from preclinical and phase I and II clinical trials, based on the authors'clinical experience and a PubMed, Cochrane library, Embase, and Google Scholar search everolimus + pancreatic cancer. Expert opinion: Everolimus has not demonstrated efficacy in PDAC; however, an mTOR inhibitor in combination with stroma-targeted therapies may be a promising area to explore in clinical trials.

Keywords: Everolimus; mTOR; pancreatic adenocarcinoma.

Figure 1. The mTOR signaling pathway

The key signaling pathway that regulates mTORC1 and mTORC2 is depicted above. mTOR is activated by signaling through the PI3K pathway, regulating cell growth, and proliferation. PTEN, TSC1, and TSC2 act as negative regulators of the mTOR pathway and inhibition of the aforementioned leads to hyperactivation of mTOR. mTOR1 signaling requires activation of the adaptor protein raptor and mTORC2, which is insensitive to acute rapamycin treatment, requires activation of rictor protein. Multiple signals from growth factors, amino acids, cellular energy status, and stress are integrated into mTORC1. Activated mTORC1 plays a major role in promoting cell growth and proliferation by stimulating various anabolic processes including protein, lipid, nucleotide synthesis, and ribosome biogenesis, and inhibiting catabolic processes such as autophagy. mTORC2 is regulated by growth factors and although mechanisms are poorly defined, it has been linked to cytoskeleton. Abbv: IRS1:Insulin Receptor substrate 1; mTOR: mammalian target of rapamycin; PDK1: 3-phosphoinositide-dependent protein kinase 1; PTEN: Phosphatase and tensin homolog; PI3K: Phosphoinositide 3-kinase; TSC1: TSC Complex Subunit 1; TSC2 TSC Complex Subunit 2; RHEB: Ras homolog enriched in brain; S6K1: Ribosomal protein S6 kinase beta-1; eIF4: Eukaryotic initiation factor 4F; 4E-BP1: eIF4E-binding protein.

Figure 2:. The mechanism of action of rapamycin and rapalogs.

Rapamycin (also known as sirolimus) is a potent immunosuppressive and anti-cancer agent that binds two proteins: FK506-binding protein (FKBP12) and FKBP-rapamycin-associated protein (FRAP). The 2.7°A structure (pdb:1FAP)¹⁸of the complex between the FRB domain of mTOR (cyan), rapamycin and FKBP12 (green) is shown. Rapamycin mediates FKBP12 dimerization with mTOR, which then blocks access to the mTOR kinase active site located in a deep cleft and hydrophobic aromatic pocket behind the FKBP12-rapamycin binding domain. Rapamycin binding to FKBP12 and subsequent selective association of the FKBP12-rapamycin complex with mTORC1 conveys highly sensitive and targeted mTORC1 inhibition. Chemical structures of sirolimus and the rapalogs (e.g. everolimus, temsirolimus, and ridaforolimus) all share a ‘central macrolide’ structure and have unique R groups at the C40 position implicating a common mechanism of mTOR inhibition [18] Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science. 1996;273(5272):239–242.