Novel therapeutic approaches for pancreatic cancer by combined targeting of RAF→MEK→ERK signaling and autophagy survival response

Faustino Mollinedo, Consuelo Gajate


KRAS (Kirsten rat sarcoma viral oncogene homolog) is a major target in pancreatic ductal adenocarcinoma (PDAC), but so far it has been perceived as “undruggable”, due to a lack of effective inhibitors. Kinsey et al. (1) have recently reported that inhibition of the RAF (rapidly accelerated fibrosarcoma)→MEK (MAPK/ERK kinase)→MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathway, downstream of KRAS, elicits autophagy as a survival response, thus protecting PDAC cells from the cytotoxic effects of RAF→MEK→ERK inhibition. MEK1/2 inhibition promotes activation of the LKB1→AMPK→ULK1 signaling axis, thus leading to pancreatic cancer cells to mount a protective survival autophagy response.