Signaling pathways in pancreatic ductile adenocarcinoma and potential therapeutic targets

Abstract

Pancreatic ductile adenocarcinoma (PDAC) has a dismal prognosis, with an overall 5-year survival of <10%. At present, PDAC is treated using systemic chemotherapeutic regimens, which have shown survival benefit in clinical trials. Unfortunately, the survival benefit offered by the current standards do not greatly impact the 5-year overall survival statistics with the disease and are associated with toxicity. The large majority of PDACs are associated with a mutation in Kirsten Ras (KRAS), which results in constative activation of downstream signaling resulting in oncogenesis, tumor progression, cellular survival, and metastasis. Due to the lack of druggable sites, designing direct KRAS inhibitors have proven difficult and extensive effort has been placed in finding upstream or downstream targets as potential therapeutic avenues. The epidermal growth factor receptor (EGFR), hedgehog (HH), and mTOR signaling pathways have all gained recent attention as potential candidates for targeted PDAC therapies. Erlotinib, an EGFR small-molecule inhibitor, has shown promise in preclinical studies against PDAC. It is currently the only Food and Drug Administration (FDA) approved targeted therapy for PDAC when used in conjunction with gemcitabine. However, clinical trials comparing erlotinib plus gemcitabine to gemcitabine alone have demonstrated only modest statistical significance in overall survival. Due to the unique hypovascular microenvironment in PDAC, designated by the term desmoplasia, the HH signaling pathway has also gained recent research interest. Recent studies have shown lithium, a divalent cation originally FDA approved for bipolar disorder, to inhibit PDAC progression through its mechanism of glycogen synthase 3 inhibition in the HH pathway. Metformin, a biguanide medication used in type II diabetes mellitus, has been shown to inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling indirectly through its activation of AMPK. Preclinical studies have demonstrated tumor regression, induction of apoptosis, and effects on the microenvironment in PDAC through the inhibition of mTORC1 by metformin. We present compelling scientific rationale, based on unique signal transduction pathways, tumor pathophysiology, and therapeutics potential for the combination of erlotinib, lithium, and metformin for the treatment of PDAC.