Abstract 4564: Therapeutic potential of SOS1 and KRAS inhibitors in malignant peripheral nerve sheath tumors
Authors: Özlem Yüce Petronczki, Laura Pisarsky, Petra Lujza Szabó, Julia Brunmair, Antonia Geyer, Norbert Kraut, Darryl McConnell, Irene Waizenegger
Journal: Cancer Research (2024)

Abstract Neurofibromatosis type 1 (NF1) is a genetic disorder that affects the nervous system. It is caused by mutations in the NF1 gene. NF1 loss of function leads to elevated RAS signaling, which plays a crucial role in cell growth and proliferation. Due to the dysregulated RAS signaling, individuals with NF1 are prone to the development of neurofibromas. These neurofibromas are typically benign and called Plexiform Neurofibromas (PNFs), in some cases, they can transform into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly aggressive and invasive cancers that contribute to a significant proportion of soft tissue sarcomas. The exact mechanisms behind this transformation are not fully understood, however it involves additional genetic mutations and alterations in cellular signaling pathways. With limited effective targeted therapies available, surgical removal remains the primary treatment option. However, due to tumor size and location, surgery may not always be feasible. The MEK inihibitor, selumetinib, has received approval for the treatment of PNFs, however some patients who were treated with selumetinib continued to develop MPNSTs suggesting that MEK inhibitors may have limitations in addressing MPNSTs. To target the RAS pathway and mitigate the effects of NF1 gene alterations, we aim to explore the therapeutic potential of two novel, potent and orally bioavailable small molecule inhibitors targeting SOS1 (BI 1701963) or KRAS (KRASmulti inhibitor BI 3706674), as alternative treatment options for MPNSTs. The KRASmulti inhibitor BI 3706674 binds non-covalently to the KRAS wild type allele as well as multiple KRAS mutant alleles in the GDP-bound state and thereby disrupts KRAS signaling. Therefore, we hypothesize that both inhibitors will work in NF1 models by reducing activated KRAS levels. In this study, a series of in vitro and in vivo experiments were conducted to evaluate the efficacy of BI 1701963 and BI 3706674 inhibitors, both individually and in combination. The studies were done in comparison to the MEK inhibitor selumetinib. In vitro analysis revealed a synergistic anti-proliferative effect when combining BI 1701963 and BI 3706674 inhibitors both in 2D and 3D growth conditions, which led to the downregulation of the RAS pathway, specifically the MAPK and PI3K signaling cascade, and an increase in apoptosis. The in vivo efficacy of either BI 1701963 or BI 3706674 inhibitor alone or in combination was tested in four different in vivo MPNST models. We observed significant tumor growth stabilization as well as tumor regression in all tested models in vivo. In-depth pathway modulation and pharmaco-dynamic studies are ongoing. In conclusion, this study highlights the combined effects of SOS1 (BI 1701963) and KRAS (BI 3706674) inhibition in MPNSTs. The combination therapy of these novel therapeutics may hold promise as a potential treatment strategy for patients with MPNSTs. Citation Format: Özlem Yüce Petronczki, Laura Pisarsky, Petra Lujza Szabó, Julia Brunmair, Antonia Geyer, Norbert Kraut, Darryl McConnell, Irene Waizenegger. Therapeutic potential of SOS1 and KRAS inhibitors in malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4564.