Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.

Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.

Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the first step of the serine synthesis pathway (SSP), is overexpressed in multiple types of cancers. The androgen receptor inhibitor enzalutamide (Enza) is the primary therapeutic drug for patients with castration-resistant prostate cancer (CRPC). However, most patients eventually develop resistance to Enza. The association of SSP with Enza resistance remains unclear. In this study, we found that high expression of PHGDH was associated with Enza resistance in CRPC cells. Moreover, increased expression of PHGDH led to ferroptosis resistance by maintaining redox homeostasis in Enza-resistant CRPC cells. Knockdown of PHGDH caused significant GSH reduction, induced lipid peroxides (LipROS) increase and significant cell death, resulting in inhibiting growth of Enza-resistant CRPC cells and sensitizing Enza-resistant CRPC cells to enzalutamide treatment both in vitro and in vivo. We also found that overexpression of PHGDH promoted cell growth and Enza resistance in CRPC cells. Furthermore, pharmacological inhibition of PHGDH by NCT-503 effectively inhibited cell growth, induced ferroptosis, and overcame enzalutamide resistance in Enza-resistant CRPC cells both in vitro and in vivo. Mechanically, NCT-503 triggered ferroptosis by decreasing GSH/GSSG levels and increasing LipROS production as well as suppressing SLC7A11 expression through activation of the p53 signaling pathway. Moreover, stimulating ferroptosis by ferroptosis inducers (FINs) or NCT-503 synergistically sensitized Enza-resistant CRPC cells to enzalutamide. The synergistic effects of NCT-503 and enzalutamide were verified in a xenograft nude mouse model. NCT-503 in combination with enzalutamide effectively restricted the growth of Enza-resistant CRPC xenografts in vivo. Overall, our study highlights the essential roles of increased PHGDH in mediating enzalutamide resistance in CRPC. Therefore, the combination of ferroptosis inducer and targeted inhibition of PHGDH could be a potential therapeutic strategy for overcoming enzalutamide resistance in CRPC.

Background: Risk and crisis communication plays an essential role in public health emergency responses. The COVID-19 pandemic has triggered spontaneous and intensive media attention, which has affected people’s adoption of personal preventive measures and their mental health.Objective: The aim of this study was to investigate the associations between exposure to COVID-19–specific information and mental health (depression and sleep quality) and self-reported compliance with personal preventive measures (face mask wearing and hand sanitizing). We also tested whether these associations were moderated by thoughtful consideration of the veracity of the information to which people were exposed.Methods: A cross-sectional, closed web-based survey was conducted among a sample of 3035 factory workers at the beginning of work resumption following the COVID-19 outbreak in Shenzhen, China. A stratified two-stage cluster sampling design was used for recruitment. Multivariate linear and logistic regression models were used for the analyses.Results: The prevalence of probable moderate-to-severe depression was 170/3035 (5.6%), while that of good or excellent sleep quality was 2110/3035 (69.5%). The prevalence of self-reported consistent face mask wearing in public places was 2903/3035 (95.7%), while that of sanitizing hands every time after returning from public spaces or touching public installations was 2151/3035 (70.9%). Of the 3035 respondents, 1013 to 1638 (33.3% to 54.0%) reported >1 hour of daily exposure to COVID-19–specific information through web-based media and television. After controlling for significant background variables, higher information exposure via television and via newspapers and magazines was associated with better sleep quality and higher compliance with hand sanitizing. Higher exposure via unofficial web-based media was associated with higher compliance with hand sanitizing but was also associated with higher depressive symptoms. In contrast, higher exposure through face-to-face communication was associated with higher depressive symptoms, worse sleep quality, and lower compliance with hand sanitizing. Exposure to information about positive outcomes for patients with COVID-19, development of vaccines and effective treatments, and heroic stories about frontline health care workers were associated with both better mental health and higher compliance with preventive measures. Higher overall information exposure was associated with higher depressive symptoms among participants who were less likely to carefully consider the veracity of the information to which they were exposed; it was also associated with better sleep quality among people who reported more thoughtful consideration of information veracity.Conclusions: This study provides empirical evidence of how the amount, sources, and contents of information to which people were exposed influenced their mental health and compliance with personal preventive measures at the initial phase of work resumption in China. Thoughtful consideration of information quality was found to play an important moderating role. Our findings may inform strategic risk communication by government and public health authorities during the COVID-19 pandemic.