Some of these molecules reduce the activity of ERK, a key protein in the cancer-promoting MAPK pathway, in human cancer cells grown in the lab, suggesting they can block signaling beyond just binding Ras.
Evidence from Studies
No evidence studies found yet.
What Would Prove This
Per GRADE and EBM methodology, here is what ideal scientific evidence would look like to definitively prove or disprove this claim, ordered from strongest to weakest.
Whether inhibition of ERK phosphorylation by Ras inhibitors correlates with clinical response in patients with KRas-mutant cancers.
A systematic review and meta-analysis of all clinical trials measuring tumor pERK levels before and after Ras inhibitor treatment, correlating the magnitude of pERK suppression with objective response rate and progression-free survival across studies.
Whether a Ras inhibitor that reduces ERK phosphorylation improves survival compared to a control in patients with KRas-mutant cancers.
A double-blind, placebo-controlled phase II trial of 150 patients with KRas-mutant cancers, randomized to receive the lead compound or placebo for 24 weeks, with primary endpoint of progression-free survival and mandatory pre- and post-treatment tumor biopsies to quantify pERK suppression by Western blot.
Whether the degree of ERK suppression in tumor biopsies predicts duration of response to Ras inhibitors in patients with KRas-mutant cancers.
A prospective cohort study of 100 patients with KRas-mutant cancers receiving a Ras inhibitor, with serial tumor biopsies collected at baseline, 24h, and 72h post-dose to quantify pERK suppression, correlated with time to progression and overall survival.
Whether non-responders to Ras inhibitors have less ERK suppression than responders in matched tumor samples.
A matched case-control study comparing 40 responders to 40 non-responders to a Ras inhibitor, matched for mutation subtype and tumor burden, analyzing pre-treatment and 24h post-dose biopsies for pERK levels by immunohistochemistry.
Whether ERK phosphorylation levels are lower in cancer cells treated with the inhibitor compared to untreated cells in the same patient sample.
A cross-sectional analysis of 50 patient-derived cancer cell lines treated with the inhibitor for 24 hours, measuring pERK levels by Western blot and comparing them to untreated controls from the same line.