Normal cells become cancerous through a set of steps that result in the continuous activity of signaling pathways that stimulate their multiplication and dissemination to other sites in the organism. A major objective of many research efforts is to identify molecules that target dysregulated pathways in the hope of restoring normalcy to the proliferation of cancer cells. One of the pathways that have emerged as of central importance in driving the unbridled multiplication of many types of cancer, including pancreatic cancer is the mTOR pathway. Inhibitors of this pathway have been identified but their therapeutic efficiency is far from optimal. The reason(s) of this limited activity is the area explored in this new paper, published in PLoS ONE, by Dr. Rozengurt, the Hirshberg Foundation Chair in Translational Pancreatic Cancer Research. The team, working with pancreatic cancer cells, have used drugs targeting the mTOR pathway and examined the activity of this pathway and other pathways known to be frequently dysregulated in pancreatic cancer. Interestingly, the block in mTOR by novel direct inhibitors not only suppressed the activity of the intended target but surprisingly, also induced robust activation of the MEK/ERK pathway, a central multiplication-inducing pathway linked to the oncogene Ras, the most commonly activated oncogene in pancreatic cancer. The first important conclusion of this manuscript is that the unexpected over-activation of a pathway like the MEK/ERK can counterbalance the inhibitory effects of the drug on its target, mTOR, thus limiting the clinical activity of these inhibitors.
Another molecule that interferes with the mTOR pathway is metformin, the most common drug used in the control of type II diabetes (T2D). There is an epidemic of T2D in the USA (> 20 million people) which is associated with obesity which in turn has increased to an alarming level. A series of recent reports, including a set of papers of papers from the Rozengurt team, indicated that metformin also inhibits the multiplication of pancreatic cancer cells, at least in part via blockade of mTOR. The new paper in PLoS ONE discovered a fundamental difference in the cellular action of metformin as compared with that of direct mTOR inhibitors in pancreatic cancer cells: metformin did not produce over-activation of the ERK pathway but instead suppressed it. If the new findings with cells in culture can be extended to cancer cells in tumors, the results could explain important aspects of the anticancer activity of different drugs that target mTOR and excitingly, suggest rational drug combinations for combating pancreatic cancer in the future.