Abstract 497: HX301, a first-in-class ARK5i, demonstrates antitumor activity in preclinical HCC models with high ARK5/Myc expression

Abstract

Abstract Introduction: Hepatocellular carcinoma (HCC) is an aggressive malignance of high mortality (6th most common worldwide) with few treatment options. Current drug treatments, including chemo-/target therapies (e.g., sorafenib), are usually ineffective among advanced HCC and with high toxicity. ARK5, or NUAK1, a novel AMP-activated protein kinase (AMPK) family member 5, is found overexpressed in many malignancies including HCC and usually associated with poor prognosis, as well as drug resistance. For example, doxorubicin, first-line chemotherapy for TACE, and transarterial chemoembolization for advanced HCC. In addition, ARK5 is found to be vitally involved in oncoprotein Myc-driven oncogenesis (metabolic homeostasis/cell survival), particularly in tumors under nutrition/oxygen-deprivations, including HCC. HX301 is a clinical stage first-in-class (FIC) ARK5 inhibitor (ARK5i) and other kinase activities (e.g., CDK4/6, CSF1R, etc.). In this study we evaluate HX301 antitumor activity in HCC over-expressing both ARK5 and c-Myc. Methods: A panel of subcutaneous HCC patient-derived xenografts (PDXs) were genomically profiled by whole transcriptome sequencing by RNAseq, and several selected models with different expression of ARK5 and c-myc expression were assessed pharmacologically using daily dosing of 100mg/kg HX301. Subcutaneous tumor responses to HX301 were calculated by tumor growth inhibition (TGI). Results: HCC PDX models LI1035, LI6610 both had high expression of ARK5 and Myc genes, whereas LI6650 had lower expression level of Myc than LI1035 and LI6610. LI6652 had lower expression level of ARK5 than LI1035 and LI6610. The log2 FPKM values of ARK5 and Myc in model of LI1035 was 3.9284 and 4.8177, 3.6629 and 5.3658 for LI6610, 3.1228 and -0.0556 for LI6650, -0.3538 and 6.5785 for LI6652. The TGI for LI1035 and LI6610 was 64% (P = 0.0293) and 62% (P = 0.0257) respectively whereas in comparison a smaller TGI of 44% (P = 0.034) was observed in LI6650. In the model of LI6652, TGI for HX301 was 58%, but a statistically significant difference was not observed when comparing the treatment group with the vehicle group (P = 0.138). Conclusions: Our preliminary results demonstrate that HX301 had strong antitumor activity in HCC PDX models expressing both ARK5 and c-Myc. HX301 has the potential to be a first-in-class ARK5i candidate for the treatment of advanced HCC with high expression of c-Myc, warranting further clinical investigation. Citation Format: Zhihua Jiao, Jingjing Wang, Hang Ke, Faming Zhang, Henry Li. HX301, a first-in-class ARK5i, demonstrates antitumor activity in preclinical HCC models with high ARK5/Myc expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 497.