image: Figure 1: Central mechanisms of MPNST progression and therapy resistance. Pathway diagram depicting NF1 loss and hyperactivation of MEK and CDK4/6 kinases as defining events in MPNST formation. FOXM1 and PD-L1 are downstream effectors of MEK and CDK4/6 whose upregulation likely mediates resistance to inhibitors of those kinases. Perpendicular bar, inhibition; Arrow, activation. Figure made with https://www.biorender.com/.
Credit: 2024 Lingo et al.
“We suggest that future therapeutic strategies targeting the oncogenic network of CDK4/6, MEK, PD-L1, and FOXM1 represent exciting future treatment options for MPNST patients.”
BUFFALO, NY- October 1, 2024 – A new mini review was published in Oncotarget's Volume 15 on September 30, 2024, entitled, “Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors.”
As highlighted in the abstract of this paper, malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Ras-driven sarcomas characterized by the loss of the NF1 tumor suppressor gene and the hyperactivation of MEK and CDK4/6 kinases. Currently, MPNSTs lack effective therapies. Recently, the authors demonstrated the remarkable efficacy of dual CDK4/6-MEK inhibition in mice with de novo MPNSTs, which was further enhanced by targeting the immune checkpoint protein PD-L1. This triple combination therapy, targeting CDK4/6, MEK, and PD-L1, resulted in prolonged MPNST regression and improved survival, although most tumors eventually developed drug resistance.
In their latest mini review, researchers Joshua J. Lingo, Ellen Voigt, and Dawn E. Quelle from the University of Iowa’s Cancer Biology Graduate Program, Holden Comprehensive Cancer Center, Medical Scientist Training Program, Department of Neuroscience and Pharmacology, and Department of Pathology, explore the immune activation phenotype caused by CDK4/6-MEK inhibition in MPNSTs, emphasizing the unique involvement of intratumoral plasma cell accumulation. They also discuss how PD-L1 and FOXM1, a tumor-promoting transcription factor, are functionally linked and may serve as key mediators of resistance to CDK4/6-MEK targeted therapies.
“We suggest that future therapeutic strategies targeting the oncogenic network of CDK4/6, MEK, PD-L1, and FOXM1 represent exciting future treatment options for MPNST patients.”
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28650
Correspondence to: Dawn E. Quelle - dawn-quelle@uiowa.edu
Keywords: cancer, MPNST, FOXM1, PD-L1, CDK4/6-MEK targeting, therapy resistance
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Journal
Oncotarget
Method of Research
Systematic review
Subject of Research
Not applicable
Article Title
Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors
Article Publication Date
30-Sep-2024
COI Statement
Authors have no conflicts of interest to declare.