Blocking ERK Signaling Inhibits Growth of Some Pancreatic Cancer Cell Lines

The GTPase KRas protein is an early player in many signal transduction pathways and performs an essential function in normal tissue signaling. The mutation of a KRAS gene is an essential step in the development of many cancers.

Investigators at the University of North Carolina (Chapel Hill, USA) discussed the effectiveness of a drug candidate that limited the growth of KRAS-mutant pancreatic cancer by inhibiting the ERK component of the RAF-MEK-ERK pathway.

RAF (rapidly accelerated fibrosarcoma) kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. RAF kinases participate in the RAS-RAF-MEK-ERK signal transduction cascade, also referred to as the mitogen-activated protein kinase (MAPK) cascade. Activation of RAF kinases requires interaction with RAS-GTPases.

ERKs (extracellular-signal-regulated kinases or classical MAP kinases) are widely expressed protein kinase intracellular signaling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

MEK (mitogen/extracellular signal-regulated kinase) is a member of the MAPK signaling cascade that is activated in some cancers. When MEK is inhibited, cell proliferation is blocked and apoptosis (controlled cell death) is induced.

The investigators reported in a paper that was published in the December 24, 2015, online edition of the journal Cancer Cell that direct chemical inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. About half of the human pancreatic cancer cell lines tested in the study responded to the ERK inhibitor. In animal models of KRAS-mutant pancreatic ductal adenocarcinoma, the drug had a significant effect on growth of tumors, causing them to shrink or impairing their progress. ERK inhibitor sensitivity was associated with MYC degradation. MYC is a regulator gene that codes for a transcription factor. The protein encoded by this gene is a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis, and cellular transformation.

“Inhibitors of other steps of this pathway have disappointingly not worked in RAS-mutant cancers because the pathway is so critical for cancer cells that they find a way to reactivate it, by reactivating ERK,” said senior author Dr. Channing Der, professor of pharmacology at the University of North Carolina. “We investigated inhibitors directly targeting ERK the last step in this pathway, in the hope that the cancer cell would have more difficulty overcoming that block. When we surveyed a large panel of pancreatic cancer cell lines, about 50% of them were responsive to the inhibitor, and about 50% of them were not responsive. That prompted two broad questions for those that responded: First of all, why did they respond, and secondly, did they acquire resistance over time?”

“We do not think that an ERK inhibitor is just the miracle drug and we are done. We believe these cancers will figure out a way to develop resistance,” said Dr. Der. “And we believe that while these ERK inhibitors may be better than existing drugs targeting this pathway in this particular cancer, to really activate a successful long-term response in the patient, we are going to have to identify another inhibitor that will work in combination with the ERK inhibitor to overcome resistance. Our guess now is that an inhibitor capable of degrading MYC might do the trick, but we are still looking for the best drug combinations.”

Related Links:
University of North Carolina