Discovery of a ‘Grail-Shaped’ Drug: Ne-ratinib and the Downregulation of Mutant RAS

Abstract

It has been stated that developing a drug that can attack mutated RAS proteins is ‘the Holy Grail’ of cancer therapeutics. Through a series of unexpected findings, the authors discovered that the irreversible epidermal growth factor receptor 1/2/4 inhibitor neratinib (HKI-272, Nerlynx®) was not only an inhibitor of those receptor tyrosine kinases, but could additionally cause receptor internalisation and degradation. To the author’s surprise, the negative control receptors c-MET and c-KIT were also degraded after neratinib exposure, albeit with a slower time-course. This appeared to be attributable to neratinib attacking receptor tyrosine kinases localised in quaternary structures. It was reasoned that neratinib had the potential to downregulate the expression of other plasma membrane localised signalling proteins, particularly RAS. In a variety of tumour types, neratinib could reduce the expression of wild type (Kirsten) and mutant (Neuroblastoma) RAS (K-RAS/N-RAS, respectively). It was subsequently demonstrated that mutant Gα proteins in uveal melanoma could also have their expression reduced by neratinib. Neratinib was shown to be an inhibitor of sterile 20 serine/threonine kinases. Acting as an inhibitor of sterile 20 serine/threonine kinases, combined with RAS inhibition, neratinib enhanced the phosphorylation and degradation of the Hippo pathway effectors yes-associated protein and transcriptional coactivator with PDZ-binding motif. In malignancies expressing a mutant K-RAS, yes-associated protein and transcriptional coactivator with PDZ-binding motif are localised in the nucleus where they cooperate with mutant K-RAS signalling to promote growth, invasion, and chemotherapy resistance. Thus, whilst neratinib is not a direct inhibitor of mutant RAS signalling, the Holy Grail, it nonetheless represents, as did the beacon atop Castle Anthrax, at least something ‘Grail-shaped’.