Abstract 1889: Allosteric inhibition of SHP2 prevents adaptive resistance to MEK inhibition in neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors

Abstract

Abstract Introduction: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are malignant sarcomas occurring in approximately 15% of NF1 patients and always develop within benign precursor lesions (plexiform neurofibromas). The mortality caused by these tumors is high, approaching 100% in patients with unresectable, metastatic or recurrent disease. Targeted inhibition of the MAP kinase (MAPK) pathway has been attempted in clinical trials using MEK inhibitors (MEKi). While emerging data demonstrate effective tumor growth inhibition in benign plexiform neurofibromas, MEK inhibition blocks MPNST progression only to a limited extent. Combination strategies targeting both the MAPK and PI3K/AKT pathways (horizontal inhibition) have had limited clinical success due to excessive toxicities which precludes delivery of optimal therapeutic concentrations. Thus, novel approaches and complementary treatment strategies that are tolerable and prevent adaptive resistance mechanisms in NF1 MPNST are urgently needed. Methods: We have succeeded in establishing orthotopic in vivo models (patient-derived human xenografts-PDXs and genetically engineered mouse models- GEMMs) via implantation of tumor cells into the sciatic nerve, an approach that is critical, because it preserves the tumor microenvironment. Furthermore, we have optimized MPNST culture conditions, allowing us to establish robust primary cultures of MPNSTs while retaining key biological features of the original tumors. Summary of findings: Using this preclinical testing platform, we demonstrate that - 1. A feedback loop mediated by induction of receptor tyrosine kinase (RTK) signaling becomes hyperactivated upon MEK inhibition (MEKi). This subsequently activates the MAPK pathway to such an extent that MEKi alone is unable to completely block signaling to ERK, thereby maintaining tumor proliferation. 2. SHP2 is a protein tyrosine phosphatase (PTP) that functions as a positive signal transducer, acting between RTKs and RAS and thus, functions as physiological mediator for RAS activation. A treatment paradigm where MEKi is combined with SHP099, an allosteric SHP2 inhibitor to counteract the rebound increase in RTK mediated signaling to RAS-MEK-ERK results in effective attenuation of MEK-ERK signaling. In vivo studies demonstrate that the drug combination exhibits synergistic effects on tumor growth inhibition and significantly prolongs survival. 3. SHP099 disrupts a functional complex (SOS1/GRB2) which is essential to RAS-GTP loading and inhibits RAS-mediated downstream MAP kinase signaling in NF1 MPNST. Conclusions - Our results provide a mechanistic context for SHP2's precise role in the regulation of RAS-GTP and demonstrate that SHP2i can prevent adaptive resistance to MEKi. Given that allosteric SHP2 inhibitors are currently in clinical trials (NCT03114319), our studies can be rapidly translated into a clinical trial to evaluate a combination of SHP2i and MEKi as a novel treatment approach in NF1-MPNSTs. Citation Format: Sameer Farouk Sait, Kwan Tang, Rebecca Brown, Daochun Sun, Xunhua Xie, Benjamin Neel, Luis Parada. Allosteric inhibition of SHP2 prevents adaptive resistance to MEK inhibition in neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1889.