A novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation is delineated and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.
Abstract
Although receptor tyrosine kinase inhibitors (sorafenib and lenvatinib) have been applied as a first-line targeted therapy for advanced unresectable hepatocellular carcinoma (HCC) for decades, their clinical efficacy is limited and the underlying mechanism remains unclear. HCC is a highly glycolytic malignancy characterized by excessive lactate accumulation in the tumor microenvironment (TME). Emerging evidences show that histone lactylation plays a critical role in various biological processes, but its function in receptor tyrosine kinase inhibitor resistance remains obscure. This study was designed to elucidate the role of histone lactylation in receptor tyrosine kinase inhibitor resistance in HCC. Clinical cohort analyses revealed that the increased nuclear pan-lysine lactylation (pan-Kla) predicts poor patient prognosis and high H4K12la level correlates with targeted drug resistance. Furthermore, lactate bidirectionally controls H4K12la through the opposing enzymatic activities of AARS1 (writer) and HDAC11 (eraser). Integrative CUT&Tag and ATAC-seq analyses demonstrated that H4K12la directly activates the promoter of RAPGEF3, a predominant upstream regulator of the RAP1 signaling pathway. Inhibition of RAPGEF3 reversed the lactate-induced targeted drug resistance both in vitro and in vivo, suggesting H4K12 lactylation modulates targeted drug resistance by activating RAPGEF3-RAP1 signaling. Notably, combining the RAPGEF3 inhibitor ESI-09 with lenvatinib synergistically suppressed HCC growth in mouse models. Clinico-pathological analyses revealed that elevated expression of the AARS1/H4K12la/RAPGEF3 axis correlated with inferior survival and sorafenib resistance in HCC patients, which was further confirmed in patient-derived xenograft (PDX) models. This study delineates a novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.
It is reported that primary HER2-specific targeted therapy (tucatinib) resistant or sensitive breast cancers derived from clinical trial patients exhibited differential protein profiles and was proposed as a promising therapeutic strategy for HER2-positive breast cancer.
It is found that the hyperlactate microenvironment induced by abnormal glycolysis in WT significantly upregulates the level of histone H3K18 lactylation (H3K18la), which promotes WT cell proliferation and migration.
Yanping Wang, Hongjie Gao, Bifei Zhang et al.· Advancement of science· 0 citations
The study identified a significant association between low TBX15 expression and sorafenib resistance in HCC and established the TBX15-cGAS/STING axis as a key regulator in HCC pathobiology.
Hui Yuan, Mengfan Jiao, Ye Sun et al.· Free Radical Biology & Medic...· 0 citations
The identification of the circTLL1-90aa/NT5C2/Ras/PI3K axis not only expands the functional repertoire of the non-coding genome but also provides new insights into the complexity of drug resistance.
Miao He, Kun-peng Li, Wan-Xia Yang et al.· Cellular Signalling· 0 citations
This study shows that elevated USP20 expression drives osimertinib resistance and is associated with poor clinical outcomes in osimertinib-resistant NSCLC, and identifies compound 89131-02-2 as a novel and selective inhibitor that targets the USP20 C154 catalytic site.
Androgen receptor pathway inhibitors (ARPIs) improve outcomes for patients with mCRPC. However, development of resistance to ARPIs is a significant clinical issue associated with the emergence of aggressive variant prostate cancer (AVPC), and consequently there is an urgent need for novel, AR pathway-independent therapies. Expression of the metalloprotease methionine aminopeptidase 2 (METAP2) has been correlated with increased mCRPC aggressiveness: high expression was reported in dedifferentiated phenotypes, including NEPC/AVPC. METAP2 regulates protein translation, post-translational modifications and has a clinically validated role inhibiting angiogenesis. METAP2 also has tumor-specific functions coordinating plasticity, vascular mimicry, and hypoxia response. Evexomostat (SDX-7320) is a prodrug of a highly potent, novel METAP2 inhibitor which has completed a phase I safety study in late-stage cancer patients (NCT02743637) and is currently being clinically investigated in patients with metastatic breast cancer (NCT05570253, NCT05455619). It was hypothesized that SDX-7320 would demonstrate anti-tumor efficacy in non-clinical prostate cancer cell-derived xenograft and patient-derived xenograft (PDX) models of ARPI-resistant CRPC and AVPC.
SDX-7320 (12 or 8 mg/kg, subcutaneous dosing, every four days) was tested in NSG mice with LNCaP xenografts in intact, castrated, and CRPC models. SDX-7320 treatment was also evaluated in LuCaP35.CR PDX xenografts in castrate mice alone as well as in combination with enzalutamide following development of resistance to enzalutamide. SDX-7320 was also tested in the LTL545, LUCAP49 and LTL331R (AR-negative, NE-positive) models of AVPC. Tumor growth was assessed and following dissection subsequently analyzed for transcriptomic (RNAseq), protein (Western blot) or histological differences (H&E staining, CD34 IHC).
SDX-7320 treatment significantly reduced tumor volume in every model and at every PC stage investigated, alone and in combination with enzalutamide (in enzalutamide-resistant tumors), as well as in the LTL545, LUCAP49 and LTL331R AVPC models. Reduced angiogenesis marker CD34 staining was observed in all tumors from SDX-7320-treated mice. Survival of mice treated with SDX-7320 was significantly enhanced, regardless of model phenotype. Downstream analyses of bulk RNAseq and proteomics showed model-specific changes to plasticity regulators c-Myc and the enhancer of zeste homolog 2 (EZH2) indicating an effect of METAP2 inhibition on prostate cancer cellular differentiation.
These results show that inhibition of METAP2 with SDX-7320 is a novel approach to treat ARPI-resistant as well as aggressive forms of prostate cancer warranting immediate clinical translation. Building upon the non-clinical data in models of AVPC presented here, combined with the body of clinical experience with SDX-7320 in past and ongoing clinical trials, planning is underway to conduct a pilot clinical trial with SDX-7320 in men with AVPC.
Peter Cornelius, Devina Laurencia, Jennifer H. Gunter, Anja Rockstroh, Benjamin A. Mayes, Pierre Dufour, Bradley J. Carver, James M. Shanahan, Colleen C. Nelson. MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B031.
Peter Cornelius, D. Laurencia, J. Gunter et al.· Clinical Cancer Research· 0 citations
