MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer CellsIn VitroandIn Vivo

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

“…Nonetheless, resistance to targeted therapies, in general, is very common in PDAC and PaCSCs. For example, MEK inhibitors are effective against PaCSCs [ 88 ], but PDAC tumors quickly adapt [ 93 ]. Thus, combinatorial approaches incorporating inhibitors of SRC kinases together with mutational profiling will likely be more effective and advantageous for the treatment of PDAC.…”

Pancreatic cancer‐derived organoids – a disease modeling tool to predict drug response

“…A threshold was set at 1.30 for CDR analysis reflecting a potent cytotoxic effect of drug. 17,18 Moreover, to have a second reliable metric to evaluate the potent drug responsiveness of PDO, we calculated the area under the curve (AUC, following the trapezoidal rule) after a drug-dose response test. This method previously showed one of the best prediction performances of real-life scenarios based on a simulation.…”

“…For this we used a set of PDX which has been previously reported to mimic the primary cancer. [16][17][18][19] PDO163 showed a more dispersed and irregular growth pattern, while PDO185 revealed a glandular growth pattern (Figure 1(a)). Cytokeratin profiles as well as proliferative capacity of PDOs and PDXs were matching (Figure 1(b) and 1(c)).…”

“…Reproducibility and power of the assay. (A) Schematic representation of PDO163 and PDO163 W/R-free isolation and propagation using pancreatic ductal organoid media respectively supplemented17 or not with WNT3A/RSPOI 8 . (B) Survival analysis of a viability assay conducted on PDO163 and PDO163 W/R-free .…”

Long‐term maintenance of functional primary human hepatocytes using small molecules

“…Thus, the functional deterioration of primary hepatocytes might be linked to the spontaneous EMT which occurs in culture. This idea is plausible, given that the components of YPAC cocktail, Y-27632 (ROCK inhibitor) [37][38][39][40], PD0325901 (MEK inhibitor) [41][42][43][44] and A83-01 (TGFb receptor inhibitor) [45][46][47] are known to suppress EMT individually or in combination with each other or other additional molecules. In contrast, CHIR99021 is implicated as an EMT inducer.…”