Abstract 1971: Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms
Authors: Xiong Yan , Liang Eric , Min Ping , Yu Huidan , Wu Bingxing , Zhai Guoqin , Yang Dajun , Zhai Yifan 
Published: March 2024

SDH deficiency, characterized by loss of SDHB, occurs in many tumors including paraganglioma, pheochromocytoma, renal, and gastrointestinal stromal tumor (GIST). Olverembatinib, a novel multikinase inhibitor, targets a broad spectrum of kinases and has promising efficacy in SDH-deficient GIST (Qiu H et al. J Clin Oncol. 2023). Here, we assessed antitumor effects of olverembatinib in preclinical models of SDH-deficient cancers and explored potential mechanisms of action (MOA). Antiproliferation assays were conducted using CellTiter-Glo®. MOA analyses were performed using western blotting. In vivo activity was evaluated using an SDHB knock-out [KO])-derived mouse xenograft model. Olverembatinib had superior antiproliferative activity (vs other approved TKIs) in SDH-deficient cell lines (IC50, 0.129-5.132 μM), including Jurkat clone E6-1 (SDHB mutation [mut]), OS-RC-2 (SDHA and SDHB mut), RKO (SDHA mut), and rat pheochromocytoma PC12 cells with SDHB KO (PC12#5F7) (Table 1). In PC12#5F7 cells, olverembatinib decreased HIF-1α, HIF-2α, VEGFA, and FGFR1 protein levels and inhibited phosphorylation of FGFR1, IGF-1R, SRC, AKT, and ERK1/2. Increased cleavage of caspase-3 and PARP-1 was observed, suggesting induction of apoptosis. In PC12#5F7 (SDHB KO)-derived xenograft models, olverembatinib demonstrated dose-dependent antitumor activity at 10 and 20 mg/kg (QOD), with tumor growth inhibition rates of 27.4% and 52.2%, respectively. At 20 mg/kg, olverembatinib showed superior efficacy vs ponatinib (10 mg/kg) and rogaratinib (50 mg/kg). Results from western blot analyses were similar in both tumor tissues and cell lines. Olverembatinib exerts promising antitumor effects in SDH-deficient neoplasms and can modulate multiple signal pathways involved in angiogenesis, apoptosis, proliferation, and survival. The results provide a preclinical rationale for future development of olverembatinib in SDH-deficient cancers.

Table 1. Antiproliferation activity of TKIs in SDH-deficient cell lines IC50 μM, mean ± SD Cell lines Acute lymphoblastic leukemia Renal cell carcinoma Colon cancer Rat pheochromocytoma carcinoma Jurkat, clone E6-1 OS-RC-2 RKO PC12 PC12#5F7 SDH status* SDHB: missense_variant, p.A15T SDHA: missense_variant, p.G184R; SDHB: stop gained, p.W218Ter SDHA: missense_variant, p.P279S SDHB competent SDHB exon 2+3 KO (heterozygote) by CRISPR-Cas9 Compound Olverembatinib (KIT, PDGFR, SRC, VEGFR, FGFR, FLT-3, RET) 0.149 ± 0.04 0.135 ± 0.083 0.129 ± 0.136 9.600 ± 1.407(n = 4) 5.132 ± 1.950 Imatinib (KIT, PDGFR) &gt; 10 &gt; 10 &gt; 10 &gt; 10 &gt; 10 Ripretinib (KIT, PDGFR) 1.559 ± 0.294 8.781 ± 1.725 1.247 ± 0.933 &gt; 10 &gt; 10 Avapritinib (PDGFRA exon 18 mut) &gt; 8.071 ± 2.728 &gt; 10 ± 0 &gt; 10 ± 0 &gt; 10 &gt; 10 Ponatinib (KIT, PDGFR, VEGFR, FGFR) 2.136 ± 2.107 0.809 ± 0.443 0.274 ± 0.241 &gt; 10 8.537 ± 3.553 Dasatinib (KIT, SRC, PDGFR, FGFR) 2.025 ± 0.644 0.029 ± 0.003 0.382 ± 0.320 &gt; 10 &gt; 10 Sunitinib (VEGFR) 4.289 ± 0.280 &gt; 5.099 ± 0.207 3.789 ± 0.385 &gt; 10 &gt; 10 Regorafenib (VEGFR) &gt; 10 5.110 ± 0.588 2.145 ± 0.812 &gt; 10 &gt; 10 Sorafenib (VEGFR) &gt; 10 3.581 ± 0.255 3.875 ± 0.170 &gt; 10 &gt; 10 Pazopanib (VEGFR, FGFR) &gt; 10 &gt; 10 &gt; 10 &gt; 10 &gt; 10 Rogaratinib (FGFR) &gt; 10 &gt; 10 &gt; 10 &gt; 10 &gt; 10 Infigratinib (FGFR) 4.581 ± 0.342 3.166 ± 0.791 2.374 ± 2.311 &gt; 10 &gt; 10 Pemigatinib (FGFR) 4.642 ± 1.842 &gt; 10 &gt; 10 &gt; 10 &gt; 10 *From CrownBio database.

Citation Format: Yan Xiong, Eric Liang, Ping Min, Huidan Yu, Bingxing Wu, Guoqin Zhai, Dajun Yang, Yifan Zhai. Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms [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 1971.