Underlying mechanisms and management strategies for regorafenib-induced toxicity in hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer cases and is the third leading cause of cancer death. Regorafenib is a multi-target inhibitor that dramatically prolongs progression-free survival in HCC patients who have failed sorafenib therapy. However, one of the primary factors limiting regorafenib's clinical utilization is toxicity.

Targeting the Wnt/β-catenin signal pathway for the treatment of gastrointestinal cancer: Potential for advancement.

Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/β-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/β-catenin signaling in GICs are currently being tested in clinical trials with promising results.

Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent.

The molecular mechanisms and targeting strategies of transcription factors in cholangiocarcinoma.

Introduction: Cholangiocarcinoma consists of a cluster of malignant biliary tumors that tend to have a poor prognosis, ranking as the second most prevalent type of liver cancer, and their incidence rate has increased globally recently. The high-frequency driving mutations of cholangiocarcinoma, such as KRAS/IDH1/ARID1A/P53, imply the epigenetic instability of cholangiocarcinoma, leading to the dysregulation of various related transcription factors, thus affecting the occurrence and development of cholangiocarcinoma. Increasingly evidence indicates that the high heterogeneity and malignancy of cholangiocarcinoma are closely related to the dysregulation of transcription factors which promote cell proliferation, invasion, migration, angiogenesis, and drug resistance through reprogrammed transcriptional networks.

SDHA/B reduction promotes hepatocellular carcinoma by facilitating the deNEDDylation of cullin1 and stabilizing YAP/TAZ.

Background And Aims: Succinate dehydrogenase enzyme (SDH) is frequently diminished in samples from patients with hepatocellular carcinoma (HCC), and SDH reduction is associated with elevated succinate level and poor prognosis in patients with HCC. However, the underlying mechanisms of how impaired SDH activity promotes HCC remain unclear.

Approach And Results: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and patient samples.

CT-707 overcomes hypoxia-mediated sorafenib resistance in Hepatocellular carcinoma by inhibiting YAP signaling.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome.

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression.

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood.

Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis.

The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis.

Post-translational modification of KRAS: potential targets for cancer therapy.

Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization.

Targeting post-translational modification of transcription factors as cancer therapy.

Dysregulated transcription factors (TFs) fuel aberrant gene expression networks, resulting in cell overproliferation, migration, and immunosuppression. Given that TFs are regarded to have vital roles in tumors, various approaches are exploited to modulate their activities. Nevertheless, except for some ligand-binding nuclear receptors, most TFs are still considered 'undruggable' targets.

USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ.

Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma. However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in hepatocellular carcinoma remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in hepatocellular carcinoma models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB.

The SIRT2-mediated deacetylation of AKR1C1 is required for suppressing its pro-metastasis function in Non-Small Cell Lung Cancer.

Aldo-keto reductase family 1 member C1 (AKR1C1) promotes malignancy of Non-Small Cell Lung Cancer (NSCLC) by activating Signal Transducer and Activator of Transcription 3 (STAT3) pathway. However, how the pro-metastatic functions of AKR1C1 are switched on/off remains unknown. : Immunoprecipitation and LC-MS/MS analyses were performed to identify the acetylation on AKR1C1 protein, and the functional analyses ( and ) were performed to depict the contribution of acetylation to the pro-metastatic effects of AKR1C1.

Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein.

Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life-threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor-β (TGF-β) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF-β pathway remains elusive.

The posttranslational modifications of Hippo-YAP pathway in cancer.

Background: Yes-associated protein (YAP) is a key effector of the Hippo pathway and is frequently dysregulated in aggressive human cancers. Aberrant YAP activation has emerged as an important driver of tumorigenesis, chemoresistance and metastasis. Since posttranslational modifications (PTMs) are pivotal modifiers that determine protein activation or subcellular localization, the malfunction of YAP due to dysregulated PTMs has been linked to various cancers.

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy.

Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers. Targeting the UPS provides a new anticancer therapeutic strategy, but clinically available UPS-targeted inhibitors, including lenalidomide and bortezomib, are limited to treat solid tumors. Under physiological conditions, deubiquitinases or deubiquitinating enzymes (DUBs) play vital roles in the UPS by removing ubiquitin from substrate proteins and regulating their proteasomal degradation and sub-localization, thus maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis.

Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis.

Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling.

AKR1C1 Activates STAT3 to Promote the Metastasis of Non-Small Cell Lung Cancer.

Metastasis is the leading cause of mortality for human non-small cell lung cancer (NSCLC). However, it is difficult to target tumor metastasis because the molecular mechanisms underlying NSCLC invasion and migration remain unclear. GEO data analyses and IHC analyses were performed to identify that the expression level of AKR1C1, a member of human aldo-keto reductase family, was highly elevated in patients with metastasis or metastatic foci of NSCLC patients.

Polysarcosine brush stabilized gold nanorods for in vivo near-infrared photothermal tumor therapy.

Unlabelled: Gold nanorods (AuNRs) are suitable candidates for photothermal therapy in vivo, because of their excellent ability to transfer near-infrared (NIR) light into heat. However, appropriate surface should be generated on AuNRs before their in vivo application because of the low colloidal stability in complicate biological environment and relatively strong toxicity compared to their pristine stabilizer cetyltrimethylammonium bromide. In the current study, polysarcosine (PS), a non-ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural α-amino acid, was used to stabilize AuNRs due to its excellent hydrophilicity and biocompatibility.

CT-707, a Novel FAK Inhibitor, Synergizes with Cabozantinib to Suppress Hepatocellular Carcinoma by Blocking Cabozantinib-Induced FAK Activation.

Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination.