Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor

Blair McNamara, Justin Harold, Diego Manavella, Stefania Bellone, Levent Mutlu, Tobias Max Philipp Hartwich, Margherita Zipponi, Yang Yang-Hartwich, Cem Demirkiran, Miguel Skyler Z. Verzosa, Kevin Yang, Jungmin Choi, Weilai Dong, Natalia Buza, Pei Hui, Gary Altwerger, Gloria S. Huang, Vaagn Andikyan, Mitchell Clark, Elena RatnerMasoud Azodi, Peter E. Schwartz, Elizabeth A. Burton, Hiroaki Inagaki, Aaron Albers, Chao Zhang, Gideon Bollag, Joseph Schlessinger, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Introduction: Uterine leiomyosarcomas (uLMS) are rare, highly aggressive tumors. Up to 30% of uLMS may harbor gain of function (GOF) in the MAP2K4 gene, important for tumor cell proliferation, differentiation and metastasis. We investigated the in vivo activity of a novel MAP2K4 inhibitor, PLX8725, against uLMS harboring MAP2K4 gene-amplification. Methods: Two fully characterized uLMS (i.e., LEY-11 and LEY-16) were grafted into female CB-17/SCID mice. Treatments with control vehicle or PLX8725 (50 mg/kg) were given via oral gavage daily on weekdays for up to 60 days. Tumor volume differences were calculated with two-way ANOVA. Pharmacokinetic (PK) and mechanistic studies of PLX8725 in uLMS PDX models were also performed. Results: Both uLMS tumors evaluated demonstrated GOF in MAP2K4 (i.e., 3 CNV in both LEY-11 and LEY-16). Tumor growth inhibition was significantly greater in both PDX LEY-11 and PDX LEY-16 treated with PLX8725 when compared to controls (p < 0.001). Median overall survival was also significantly longer in both PDX LEY-11 (p = 0.0047) and PDX LEY-16 (p = 0.0058) treatment cohorts when compared to controls. PLX8725 oral treatment was well tolerated, and PK studies demonstrated that oral PLX8725 gives extended exposure in mice. Ex vivo tumor samples after PLX8725 exposure decreased phosphorylated-ATR, JNK and p38, and increased expression of apoptotic molecules on western blot. Conclusion: PLX8725 demonstrates promising in vivo activity against PDX models of uLMS harboring GOF alterations in the MAP2K4 gene with tolerable toxicity. Phase I trials of PLX8725 in advanced, recurrent, chemotherapy-resistant uLMS patients are warranted.

Original languageEnglish
Pages (from-to)65-71
Number of pages7
JournalGynecologic Oncology
Volume172
DOIs
Publication statusPublished - 2023 May

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • MAP2K4
  • MAP2K4 inhibitors
  • PLX8725
  • Uterine leiomyosarcoma

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

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