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Review
. 2024 Sep 30:15:638-643.
doi: 10.18632/oncotarget.28650.

Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors

Joshua J Lingo  1   2 , Ellen Voigt  1   2   3 , Dawn E Quelle  1   2   3   4   5
Affiliations
Review

Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors

Joshua J Lingo et al. Oncotarget. .

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Ras-driven sarcomas characterized by loss of the NF1 tumor suppressor gene and hyperactivation of MEK and CDK4/6 kinases. MPNSTs lack effective therapies. We recently demonstrated remarkable efficacy of dual CDK4/6-MEK inhibition in mice with de novo MPNSTs, which was heightened by combined targeting of the immune checkpoint protein, PD-L1. The triple combination therapy targeting CDK4/6, MEK, and PD-L1 led to extended MPNST regression and improved survival, although most tumors eventually acquired drug resistance. Here, we consider the immune activation phenotype caused by CDK4/6-MEK inhibition in MPNSTs that uniquely involved intratumoral plasma cell accumulation. We discuss how PD-L1 and FOXM1, a tumor-promoting transcription factor, are functionally linked and may be key mediators of resistance to CDK4/6-MEK targeted therapies. Finally, the role of FOXM1 in suppressing anti-tumor immunity and potentially thwarting immune-based therapies is considered. 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.

Keywords: CDK4/6-MEK targeting; FOXM1; MPNST; PD-L1; therapy resistance.

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Conflict of interest statement

CONFLICTS OF INTEREST

Authors have no conflicts of interest to declare.

Figures

Figure 1
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/.
Figure 2
Figure 2. Hallmark features of CDK4/6 and MEK inhibitor resistance and FOXM1 elevation in tumors.
Venn diagram indicating the shared (middle) and unique (left and right) features of each setting. Figure made with https://www.biorender.com/.
See this image and copyright information in PMC

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