Overcoming Resistance to Targeted Anticancer Therapies through Small-Molecule-Mediated MEK Degradation

Abstract

The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL). Caspase-3-mediated degradation of MEK kinases results in sustained pathway inhibition and substantially delayed or eliminated resistance in cancer cells in a manner far superior to combinations with MEK inhibitors. These data suggest the generality of drug-mediated MEK kinase cleavage as a therapeutic strategy to prevent resistance to targeted anticancer therapies.

Chemoresistance and the Self-Maintaining Tumor Microenvironment

“…Bcl-2 is a target protein of chemotherapeutics such as paclitaxel [27]. The MAPK pathway component MEK1/2 is inhibited by the targeted therapeutics trametinib and cobimetinib, but the development of secondary mutations can lead to the circumvention of this therapy [28].…”

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential

“…This protein degradation strategy sustains inhibition of MEK and the MAPK pathway and delays the onset of resistance. 207 (E) Time course of phosphorylated MEK1/2 levels upon treatment of vemurafenib (BRAF v600E inhibitor, Vem), PAC-1, trametinib (MEK1/2 inhibitor, Tram), and combinations as indicated. Experiment was conducted with A375 cells (BRAF v600E cell line).…”

Fighting Kinase Drug Resistance with Caspase Activators

“…The approach described by the Hergenrother group (Peh et al, 2018) makes use of the same physiological process: imposing dual pressure in the MAPK pathway. Activation of procaspase-3 by PAC-1 leads to caspase-3 cleavage of MEK1/2 (Figure 1), which eliminates the function of MEK1/2.…”

“…The authors focused on naive cancer cell lines as well as lines that had already developed resistance to a first generation PKI therapeutic. In particular, this work by Peh et al (2018) focuses on BRAF V600E (which is targeted by vemurafenib), EGFR T790M (which is targeted by osimertinib), EML4-ALK (which is targeted by ceritinib), or BCR-ABL (which is targeted by imatinib). In all cases, cells treated with PKI alone developed resistance earlier than in combination with PAC-1 or trametinib, underscoring the prior observation that blocking the MEK1/2 control point is an effective co-strategy for preventing emergence of drug resistance.…”

“…The findings of Peh et al (2018) suggest that new combination therapies using PAC-1, which eliminate key components of the MAPK pathway, stand to dramatically prolong the utility of kinase inhibiting drugs. The fact that co-administration of procaspase-3 activators (at levels that have been shown to be clinically achievable) worked on four different cell types indicates that this approach may be broadly applicable across cancers that achieve their proliferative state through a number of different mutations in a wide variety of pathways, including the MAPK pathway.…”