Uterine Leiomyosarcomas harboring MAP2K4 gene amplification are markedly sensitive in vivo to PLX8725, a Novel MAP2K4 Inhibitor

초록

Objectives Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive tumor with an estimated 5-year overall survival of 50% for even early-stage disease. Up to 30% of uLMS may harbor a gain of function in the MAP2K4 gene, a member of the MAPK family which plays an important role in tumor cell proliferation, differentiation, and metastasization. We sought to investigate the in vivo activity of a novel MAP2K4 inhibitor, PLX8725, against uLMS harboring MAP2K4 gene amplification. Methods Whole exome sequencing (WES), RNA-sequencing, and/or whole-genome sequencing were performed on a total of 83 patients from local and TCGA data; two patient-derived xenografts (PDX) had WES data abstracted. Available PDX models (LEY11 and LEY16) were grafted into female CB-17/SCID mice and triaged for treatment with a control vehicle or PLX8725 (50 mg/kg daily). Treatments were given via oral gavage Monday to Friday twice daily for up to 60 days, and tumor measurements, as well as weights, were obtained twice weekly. Tumor volume differences were calculated with a two-way ANOVA, and a P-value of <0.05 was considered statistically significant. Overall survival was compared via Kaplan-Meier survival analysis. Results Of 83 available samples, 30.2% demonstrated MAP2K4 gene amplification. Both uLMS PDX models available demonstrated a gain of function in MAP2K4 (i.e., 3 CNV in both LEY11 and 16 PDX). Tumor growth inhibition was significantly greater in the PLX8725 groups in both LEY11 and LEY16 when compared to controls (P = 0.002 and P = 0.001, respectively). Overall survival was also significantly longer in both LEY11 (P = 0.004) and LEY16 (P < 0.001) treatment cohorts when compared to control mice. PLX8725 oral treatment was well tolerated in SCID mice for up to 60 days. Conclusions PLX8725 demonstrates promising in vivo activity against PDX models of uLMS that harbor gain of function alterations in the MAP2K4 gene with tolerable toxicity. Phase I trials of PLX8725 in advanced, recurrent, chemotherapy-resistant uLMS patients are warranted.