Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

Abstract

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.

Keywords: DNA repair; autophagy; epigenetic alterations; immunotherapy; key mutations; pancreatic ductal adenocarcinoma; therapies; tumor microenvironment.

Figure 1

Targeting key signaling pathways in patients with pancreatic ductal adenocarcinoma (PCa). EGFR, epidermal growth factor receptor; RAS, rat sarcoma viral oncogene; AKT, protein kinase B; CDK4/CDK6, cyclin-dependent kinase 4/6; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinases; PI3K, phosphoinositide 3-kinase; mTOR, mechanistic target of rapamycin; FAK, focal adhesion kinase; BTK, Bruton’s tyrosine kinase.

Figure 2

Targeting metabolic reprogramming in patients with PCa. KRAS-mutant tumors rely on metabolic reprogramming, exposing critical vulnerabilities to target for therapy. MCT1/2, monocarboxylate transporters 1/2; ACSL3, acyl-CoA synthetase long-chain 3.

Figure 3

Targeting immune regulatory networks in PCa patients. Some of the current actionable interventions for pancreatic cancer.