Editors' ChoicePancreatic Cancer

Taking the Road Less Traveled: RAS Meets PI3K/PDK1

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Science Translational Medicine  03 Apr 2013:
Vol. 5, Issue 179, pp. 179ec56
DOI: 10.1126/scitranslmed.3006204

The power and complexity of the human mind is enormous. Inevitably, however, we seem to lapse into a reductionist view of both the world and of science. People are either “good” or “bad”; an individual must either be a Republican or a Democrat; and RAS signals through RAF-MEK-ERK, whereas phosphatidylinositol 3-kinase (PI3K) signals through PDK1-AKT-FOXO1. Although reductionism is useful in allowing us to experimentally test hypotheses and reduce our scientific studies to single-variable experiments, it can also lead us down the wrong road or pathway.

Work by Eser and colleagues in pancreatic cancer—one of the most lethal and treatment-resistant neoplasms—has now elucidated a major therapeutically targetable effector pathway of RAS signaling, and, surprisingly, it is the PI3K/PDK1 axis. Through a series of sophisticated genetic loss-of-function experiments in mouse models, this group was able to show a complete dependence of KRAS-driven pancreatic tumorigenesis on PI3K/PDK1 signaling. These studies used conditional tissue-specific deletion of individual effectors of the RAS and PI3K signaling pathways to precisely dissect the relative contributions of each gene and protein to overall tumor development and progression in vivo. Furthermore, the authors demonstrated that unlike RAS-driven pancreatic cancer, lung tumors harboring activated RAS depend on canonical MAPK signaling through RAF and not PI3K/PDK. These findings provided the rationale for the study of PI3K inhibitors for the treatment of RAS-driven pancreatic tumors. Consistent with the observation that activated RAS signals through PDK1/PI3K in pancreatic cancer, treatment of immortalized patient-derived cells and mouse models with these inhibitors resulted in marked therapeutic activity.

The ability to translate these findings to the clinic will be greatly accelerated by the fact that this class of drugs is already in phase II clinical trials for other disease indications. Although the ultimate translation of these findings from mouse models to patients suffering from this deadly disease remains to be seen, all things considered maybe there is something to what Robert Frost wrote about taking the road less traveled.

S. Eser et al., Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23, 406–420 (2013). [Abstract]

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