Truong on the Rationale for Investigating ERK2 Substrate Binding Modalities in MPNs

Billy Truong, PhD candidate, Fox Chase Cancer Center, discusses the rationale for investigating the functions of ERK2 substrate binding modalities in myeloproliferative neoplasms (MPNs).

Truong and colleagues are conducting research investigating cell signaling programs that are altered in MPNs. Specifically, treatment resistance often arises from the activation of the MAPK pathway, Truong says. Approximately 85% of cancers have genetic modifications in proteins, especially in the RAS protein, which ultimately drive uncontrolled tumor cell proliferation, Truong explains.

Downstream of the MAPK pathway is the ERK2 protein, which is a common target of cancer therapies, Truong notes. However, drugs that target the kinase function of ERK2 are traditionally designed to be nonspecific and are therefore toxic to healthy cells expressing ERK2, Truong emphasizes. Accordingly, drug specificity remains an unmet need for patients with MPNs.

Investigators initiated research examining the interactions between kinases and their binding sites to determine whether those interactions could be attenuated to disable cancer progression, according to Truong. D and DBP were found to be 2 substrate binding domains of ERK2 that have divergent roles in MPN pathogenesis. ERK2 DBP mitigates MPN pathogenesis and promotes oncogene-induced senescence, and ERK2 D promotes disease progression via induction of Polq.

This research uses mouse models, as well as models based on small molecule inhibitors that specifically target the substrate binding domains of ERK2, Truong says. Tumor samples include primary samples from mice that mimic diseases seen in humans, as well as patient-derived cells, Truong adds.

The goal of this research is to develop a treatment regimen that can be used in clinical practice for patients with MPNs, which are incurable, Truong explains. Currently, most therapies for patients with MPNs target symptoms, but are not curative, Truong notes. This research indicates that a Polq inhibitor combined with an ERK2 D inhibitor may overcome treatment resistance for patients with MPNs.