Author: TheNeelLab

The RAS/ERK MAP kinase pathway is aberrantly activated in a large percentage of human cancers, and promotes malignant behavior.  Inhibitors of MEK, one of the key intermediates in this pathway, have had limited utility in the clinic, often due to the rapid development of “intrinsic resistance.”  Intrinsic resistance is due to up regulation of multiple growth factor receptors and their ligands, and previous work by the lab and by others has shown that is required for RAS activation by these receptors.  Here we found that combining MEK and SHP2 inhibitors shows broad efficacy against a wide range of malignancies, and also that SHP2 inhibitors as single agents can antagonize certain types of RAS mutations (fast cycling mutants).

SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models.
Cancer Discov. 2018 Oct;8(10):1237-1249.

Mutations of one copy of TET2, whose protein product promotes DNA (and RNA) hydroxymethylation (and eventually, DNA and RNA de-methylation, are commonly associated with myelodyspastic syndromes (MDS) and acute myeloid leukemia, among other hematopoietic neoplasms. Previous work had suggested that Vitamin C, an essential co-factor of TET2, can promote TET2 activation as well.  We found that high dose vitamin C, acting via residual TET2 and TET3, had potent anti-neoplastic effects in mouse and human models of MDS/AML. Molecular analysis confirmed that this treatment promotes demethylation of key leukemia-associated genes, including base excision repair genes. The latter result suggested that PARP inhibitors might further increase Vitamin C efficacy, which we also demonstrated.

Vitamin C in Stem Cell Reprogramming and Cancer
Trends Cell Biol. 2018 Sep;28(9):698-708.