CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression

Abstract

Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting CDK4/6, MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. Experimental Design: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNAseq, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDXs), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. Results: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. Conclusions: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.

Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors

“… 49 Additionally, there is a growing interesting in immunotherapeutic approaches in the treatment of MPNST, alone or in combination with molecularly targeted therapies, although no clinical trials have demonstrated overall benefits of immune checkpoint blockade (ICB) to date in MPNST. Novel approaches used in preclinical models that have shown efficacy include the combination of ICB with CDK4/6 and MEK inhibition 50 and the use of virus-based immunotherapy. 51 There is an ongoing phase I clinical trial studying the use of neoadjuvant nivolumab plus ipilimumab for newly diagnosed MPNST (NCT04465643).…”

FOXM1, MEK, and CDK4/6: New Targets for Malignant Peripheral Nerve Sheath Tumor Therapy

“…A role for RABL6A in Schwann cell biology is relevant to PNF and MPNST development, since Schwann cells are the non-transformed precursors of those tumors. In addition, RABL6A is a critical activator of MEK-ERK signaling [99,104], and its overexpression in patient MPNSTs is significantly associated with an activated Ras-MEK pathway [105]. Finally, in biomarker analyses of 163 sarcomas representing many different histological types, RABL6A expression was positively correlated with high levels of p53 (likely mutated) and YAP [92].…”

“…We recently sought to identify new drug combinations, which would have sustained activity against MPNSTs. We began by querying the Connectivity Map (C-Map) database [125] using transcriptomes gathered from patient MPNSTs [105]. Consistent with molecular data from patient tumors, which defined hyperactivated MEK and CDK4/6 as hallmark drivers of MPNSTs, small molecule drugs targeting MEK and CDK4/6 were among the top drug candidates identified.…”

“…We previously found that CDK4/6 inhibitor monotherapy had excellent anti-tumor effects against de novo MPNSTs in mice, but drug resistance occurred rapidly [93]. In the most recent study, MEK inhibitors alone were ineffective, but low-dose combinations of a MEK inhibitor (mirdametinib) and CDK4/6 inhibitor (palbociclib) acted synergistically in causing remarkable tumor regression and improved survival in immune competent mice bearing MPNSTs [105]. Excitingly, dual MEK-CDK4/6 inhibition induced an anti-tumor immune response, which sensitized MPNSTs to immune checkpoint inhibitor therapy using anti-PD-L1 (programmed death-ligand 1) therapy, with about 10% of mice showing cure with long-term treatment.…”

The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation

“…A preclinical model of MPNST development demonstrated that combined cyclin-dependent kinase 4/6 (CDK4/6) and MEK inhibition sensitized MPNST to anti-PD-L1 immune checkpoint blockade (ICB) [ 117 ]. Case studies have reported deep and/or or complete responses to pembrolizumab, a PD-1 receptor inhibitor, in the treatment of PD-L1 positive relapsed/refractory MPNST [ 118 , 119 , 120 ], and several clinical trials of ICB in MPNST are currently underway.…”