Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics

Abstract

Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and survival signaling. As efforts to target RAS and its downstream effectors continue, parallel research aimed at identifying novel targets is also needed in order to improve therapeutic options and efficacy. Recent studies demonstrate that self-renewing cancer stem cells (CSCs) contribute to metastatic dissemination and therapy failure, the causes of mortality from PDAC. Here, we discuss current challenges in PDAC therapeutics, highlight the contribution of mesenchymal/CSC plasticity to PDAC pathogenesis, and propose that targeting the drivers of plasticity will prove beneficial. Increasingly, intrinsic oncogenic and extrinsic pro-growth/survival signaling emanating from the tumor microenvironment (TME) are being implicated in the de novo generation of CSC and regulation of tumor cell plasticity. An improved understanding of key regulators of PDAC plasticity is providing new potential avenues for targeting the properties associated with CSC (including enhanced invasion and migration, metastatic outgrowth, and resistance to therapy). Finally, we describe the growing field of therapeutics directed at cancer stem cells and cancer cell plasticity in order to improve the lives of patients with PDAC.

Keywords: cancer stem cells; cell plasticity; epithelial–mesenchymal transition; oncogenes; therapeutics; tumor microenvironment.

Figure 1

Epithelial/non-stem cell to mesenchymal/cancer stem cell plasticity. Epithelial/non-cancer stem cells retaining cell plasticity respond to environmental or intrinsic cues by fluidly transitioning through intermediary stages until reaching a mesenchymal/cancer stem cell state. These intermediary states hold immense plasticity and are the roots behind metastatic dissemination and therapeutic failure. CSC: cancer stem cell.

Figure 2

Targeting de novo mesenchymal/cancer stem cell (Mes/CSC) plasticity. Epithelial/non-cancer stem cells acquire mutations within oncogenes or are exposed to extrinsic factors capable of driving them to a mesenchymal/CSC (Mes/CSC) state. This Mes/CSC plasticity imparts increased migration and metastases, tumor initiation, and importantly therapeutic resistance. In order to combat this cell plasticity, one can utilize neutralizing antibodies targeting extrinsic drivers (i.e., Oncostatin M (OSM), Transforming Growth Factor-β (TGF-β), Tumor Necrosis Factor-α (TNF-α)), and blocking peptides or small molecules targeted toward intrinsic drivers (i.e., Family with Sequence Similarity 83 Member A (FAM83A), KRAS, PI3K) of cell plasticity to prevent Mes/CSC induction or revert the Mes/CSC state into a more drug sensitive epithelial/non-CSC state. TME: tumor microenvironment.