A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells

Pancreatic Cancer is one of the most lethal Cancer types and is becoming a leading cause of cancer-related deaths. The limited benefit offered by chemotherapy agents has propelled the search for alternative approaches that target specific molecular drivers of Cancer growth and progression. Mutant KRas and effector pathways Raf/MEK/ERK and PI3K/Akt are key players in pancreatic cancer; however, preclinical studies have shown adaptive tumour response to combined MEK and PI3K kinase inhibition leading to treatment resistance. There is a critical unmet need to decipher the molecular basis underlying adaptation to this targeted approach. Here, we aimed to identify common protein expression alterations associated with adaptive resistance in KRas-mutant pancreatic Cancer cells, and test if it can be overcome by selected already available small molecule drugs. We found a group of 14 proteins with common expression change in resistant cells, including KRas, caveolin-1, filamin-a, eplin, IGF2R and cytokeratins CK-8, -18 and -19. Notably, several proteins have previously been observed in pancreatic Cancer cells with intrinsic resistance to the combined kinase inhibition treatment, suggesting a proteomic signature. We also found that resistant cells are sensitive to small molecule drugs ERK Inhibitor GDC-0994, S6K1 inhibitor DG2 and statins.

MEK and PI3K; kinase inhibition; pancreatic cancer; proteomics; resistance.