The triptolide derivative MRx102 inhibits Wnt pathway activation and has potent anti-tumor effects in lung cancer

Abstract

vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (6 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 24 ALKþ NSCLC pts treated at doses 200 mg are evaluable for response; partial response (PR) was achieved in 16 pts (67%) and stable disease (SD) in 3 pts (13%). In the crizotinib-naïve pts (n¼8), responses were observed in 6 pts (75%) and SD in 1 pt (13%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naïve and crizotinib resistant pts. The median duration of treatment in the 24 evaluable ALKþ pts is 23.8þ weeks, with the longest being 112þ weeks.Conclusion: X-396 is well-tolerated and induces responses in both crizotinib-naïve and crizotinib-resistant ALKþ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.

Triptolide inhibits Wnt signaling in NSCLC through upregulation of multiple Wnt inhibitory factors via epigenetic modifications to Histone H3

“…Along with H3 de‐methylation, we observed significant increase in expression of multiple Wnt inhibitory factors including WIF1, FRZB, SFRP1, ENY2, and DKK1 after triptolide treatment. Our previous work showed the triptolide derivative MRx102 upregulated WIF1 in lung cancer cell lines through promoter hypomethylation . However, we did not observe this same phenomenon at any of the promoter regions of the five Wnt inhibitory factors studied even at low doses of triptolide (data not shown).…”

“…We sought to evaluate if triptolide is inducing cellular arrest and eventual apoptosis through activation of these Wnt inhibitory factors. Our research previously showed the triptolide derivative MRx102 induces its effects in lung cancer cells in part by increasing expression of Wnt inhibitory factor 1 (WIF1) . Other studies have demonstrated triptolide modulates the methylation status of H3 at several key lysine residues in multiple myeloma .…”

“…Cell lysates were prepared in Laemmli sample buffer and analyzed by immunoblotting as previously described …”