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

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. This might explain, at least in part, the lack of clinical benefit of MEK1/2 inhibitors (e.g., trametinib, pimasertib) in PDAC patients, as assessed by the absence of a statistically significant improvement in overall survival (2,3), and might suggest a treatment strategy, involving inhibition of both RAF→MEK→ERK signaling and autophagy, for PDAC and other RAS-driven cancers (1). This is of importance because there is an urgent need to establish new frameworks to improve future treatments as, despite intensive research over the past several years, prognosis of PDAC remains gloomy, with no effective therapeutic treatment and with median survivals of less than a year