Understanding and targeting MAPK pathway activation in NF1-deficient malignant peripheral nerve sheath tumor (MPNST)

点击翻译按钮获取中文摘要

Project Abstract Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft tissue sarcomas that occur in distinct clinical settings: neurofibromatosis 1 (NF1)-associated (45%), sporadic (45%) or radiotherapy (RT)-associated (10%). MPNSTs metastasize early and are resistant to radiotherapy and systemic chemotherapy and have poor prognosis. Irrespective of the clinical settings, MPNSTs share the same molecular pathway inactivation in NF1 (>90%, hence NF1-deficient), Polycomb repressive complex 2 (PRC2), and CDKN2A through biallelic genetic alterations, suggesting that they can be molecularly targeted similarly. NF1- deficient plexiform neurofibroma responds well to MEK inhibitor (MEKi) treatment clinically; however, NF1- deficeint MPNSTs arising from plexiform neurofibromas are universally resistant to MEKi, suggesting intrinsic resistance in the more aggressive form of peripheral nerve sheath tumors. Using MPNST patient tumor samples and preclinical MPNST models, we have uncovered that PRC2-loss leads to PDGRA upregulation; MEKi treatment resulted in feedback upregulation of PDGFRB irrespective of the PRC2 status. The convergence of the PDGFR pathway activation by different mechanisms points to a novel therapeutic opportunity to target the PDGFR pathway to overcome MEKi resistance in MPNST. Combination of a novel PDGFRA/B inhibitor, ripretinib with a MEKi leads to synergistic growth inhibition of MPNST in vitro and in vivo. We hypothesize that PDGFRA/B pathway activation represent a central resistance mechanism to MEKi and combined targeting of the PDGFR and MAPK pathways with ripretinib (pan-PDGFRA/B inhibitor) and binimetinib (MEKi) may present an effective therapeutic strategy in NF1-deficient MPNST. Here, we propose to investigate the tumor heterogeneity and cellular plasticity involved in tumor evolution and adaptive resistance to binimetinib and combination of ripretinib and binimetinib, using well-defined preclinical MPNST in vitro and in vivo model systems and single-cell analysis including single cell RNA-seq (scRNA-seq) and a novel barcoding system. Additionally, we propose a collaborative clinical investigation between CCR/NCI (Drs. Widemann/Shern) and MSKCC (Dr. Chi) to conduct a proof-of-concept phase I/II study of the combination of ripretinib and binimetinib in patients with NF1-deficient MPNST. In this trial, we will assess and optimize the evaluation of MAPK pathway inhibition to the ripretinib/binimetinib combination therapy using traditional ERK phosphorylation and newly established custom Pea3-family ETS-regulated MAPK signature. Further, we will also investigate the tumor heterogeneity and cellular plasticity in tumor evolution and resistance mechanisms to the ripretinib/binimetinib combination using targeted NGS, scRNA-seq and integrative analysis. The proposal leverages the synergistic expertise and resources at MSKCC and CCR/NCI. We believe that these studies will generate mechanistic insight of therapeutic resistance and provide the pivotal clinical and translational information for future definitive trials, with the potential to change the clinical practice in MPNST.