Abstract P125: Combined inhibition of SHP2 and CDK4/6 is active in NF1-associated malignant peripheral nerve sheath tumor

Abstract

Abstract Background: NF1 is an essential negative regulator of RAS activity and is altered in nearly 90% of malignant peripheral nerve sheath tumors (MPNST). Additional recurrent molecular changes include loss of function alterations in CDKN2A, TP53, EED and SUZ12, but molecular targeting of these genomic events represents a unique challenge. We previously reported that the efficacy of MEK inhibitor is limited by adaptive activation of receptor tyrosine kinases and the adaptor protein SHP2, and that combined inhibition of MEK and SHP2 is effective in MPNST. Loss of CDKN2A, inactivation of RB1, and hyperactivation of cyclin dependent kinases (CDK) in MPNST also suggest that small-molecule CDK4/6 inhibitors (CDK4/6i) may be a potential therapeutic strategy, but monotherapy with CDK4/6i also demonstrates limited activity. Given the dependency of D-cyclins on RAS signaling, we hypothesize that the anti-tumor effects of CDK4/6i may be potentiated by agents (SHP2i) targeting the upstream activators of RAS. Methods: The effects of shRNA-mediated inducible SHP2 knockdown on RAS signaling, short-term and long-term cell growth, and response to CDK4/6i were examined using immunoblotting, high throughput proliferation assays, and colony formation assays. Combined effects of SHP2i plus CDK4/6i on signaling, cell and tumor growth were assessed. Pharmacodynamic (PD) assays were performed on tumors extracted following drug treatment in patient-derived xenograft (PDX) models. Results: Despite a modest effect of SHP2 knockdown on ERK signaling, shSHP2 reduced MPNST cell growth. SHP2 knockdown or SHP2i treatment alleviated activation of ERK signaling and cyclin D1 expression induced by CDK4/6i, and enhanced the sensitivity to CDK4/6i. Combination benefit was observed in in vitro cell growth and in vivo PDX. Although some PDX models demonstrated similar responses to SHP2i alone or SHP2i + CDK4/6i during the initial 4 weeks on treatment, we found more sustained growth inhibition exerted by the combination. PD studies demonstrated a decrease in p-ERK levels in tumors treated with either SHP2i alone or the SHP2i/CDK4/6i combination. Conclusions: Our preliminary data demonstrate that the combined inhibition of SHP2 and CDK4/6 is active and produces durable response in models of NF1-associated MPNST. This combination strategy may represent a novel treatment strategy for patients with MPNST. Citation Format: Jiawan Wang, Ana Calizo, Kai Pollard, Angela C. Hirbe, Christine A. Pratilas. Combined inhibition of SHP2 and CDK4/6 is active in NF1-associated malignant peripheral nerve sheath tumor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P125.