CDK4/6 inhibition becomes effective in preclinical models of melanoma when combined with MDM2 antagonism.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 ⁺ T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

Purpose: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN, and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy. Experimental Design: To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein–phosphoprotein changes, were analyzed. Results: One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAFV600WT tumors responded to KRT-232 treatment alone while BRAFV600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors. Conclusions: KRT-232 is an effective therapy for the treatment of either BRAFWT or PANWT (BRAFWT, NRASWT) TP53WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAFV600-mutant tumors.

Objectives: Soft tissue sarcomas are a group of tumors derived from the mesenchymal origin. Historically, they have been classified according to morphologic and immunohistochemical characteristics. The advent of multiplexed next-generation sequencing (NGS), specifically RNA sequencing, has modified the classification of such tumors and others by determining categorization based on molecular alterations. The NUTM1 rearrangement, previously thought to be present only in carcinomas, has recently been reported in poorly differentiated high-grade sarcomas of the soft tissue. We present the first reported case of an epithelioid hyalinizing sarcoma harboring the MGA-NUTM1 fusion in an acral site.Methods: Histopathologic, immunohistochemical, and molecular testing were performed on resection tissue.Results: Histologically, the tumor showed an epithelioid morphology with prominent background hyalinization. Immunohistochemically, the tumor expressed CD99 and nuclear NUT-1. By NGS the tumor harbors MGA-NUTM1 fusion.Conclusions: Our findings support more extensive use of NGS for accurate sarcoma classification and identification of potential therapeutic targets. Furthermore, they corroborate the fact that NUTM1-rearranged soft tissue tumors represent a spectrum of heterogeneous morphologic entities. This case also highlights the utility of NUT-1 immunohistochemical study as a possible screening tool for NUTM1-fused sarcomas.