In the above-mentioned article published in Current Cancer Drug Targets, 2026, 26(4), 393-395, the citation for Fig. (1) was inadvertently omitted. The original article can be found online at: https://www.benthamscience.com/article/150331 Details of the correction are as follows: Original: These findings suggested that the metabolic features associated with metastasis could be utilized as potential therapeutic targets. The authors proposed that, for cancer cells, oxidative metabolism could play an ad-vantageous role in the process of metastasis. However, the exact molecular events underlying increased metastatic burden are unclear and require further investi-gation. Corrected: These findings suggested that the metabolic features associated with metastasis could be utilized as potential therapeutic targets. The authors proposed that, for cancer cells, oxidative metabolism could play an ad-vantageous role in the process of metastasis. However, the exact molecular events underlying increased metastatic burden are unclear and require further investigation (Fig. 1).

Lung cancer remains one of the major causes of cancer-related mortality. Thus, newer therapeutic approaches are urgently needed. Because cancer is a metabolic disease, lung cancer cells have also rewired their metabolism to gain growth advantage and support survival. Therefore, the use of metabolic stress-inducing agents as a therapeutic strategy for lung cancer is an attractive idea. In this study, we have investigated the anticancer potential of CB-839 and metformin. CB-839, a selective glutaminase-1 inhibitor, creates glutamine-deficient conditions, and metformin is an antidiabetic drug. We report that CB-839 and metformin induce metabolic stress and inhibit growth of human lung cancer cells. Of note, lung cancer cells that harbor mutant K-Ras are more sensitive to these agents compared to cells with wild-type K-Ras status. In the K-Ras mutant cells, these agents induce cell death partly, via death receptor 5 (DR5)-dependent extrinsic pathway. However, in the lung cancer cells harboring wild-type K-Ras, these agents activate autophagy without significant effect on DR5 regulation. Pretreatment of K-Ras wild-type cells with autophagy inhibitor improves the anticancer potential of these agents coupled with activation of DR5-dependent pathway. Our results further show that the growth inhibitory effects of these agents appear to be linked to the mutant K-Ras status because pan-K-Ras inhibitor that inhibits the mutant K-Ras proteins blunted the growth inhibitory effects of these agents in cells harboring mutant K-Ras. Collectively, our results provide valuable new insights into exploiting the metabolic rewiring of lung cancer cells by using metabolic stress-inducing drugs as an important therapeutic approach. SIGNIFICANCE STATEMENT: Anticancer potential of CB-839 and metformin is investigated in lung cancer. These agents induce cell death partly, via death receptor 5-dependent pathway, and a relationship with K-Ras status of lung cancer cells is noted. Lung cancer cells with mutant K-Ras are more sensitive compared to cells with wild-type K-Ras. Autophagy inhibition of K-Ras wild-type cells improves the anticancer potential. This study provides new insights into exploiting the metabolic rewiring of lung cancer cells as an important therapeutic strategy.

Lung cancer is responsible for high morbidity and mortality worldwide. In general, lung cancer can be divided into two major types, including small cell lung carcinoma (SCLC) and the more common non-small cell lung carcinoma (NSCLC). Molecular events underlying lung cancer development, growth, and progression remain complex. In addition to a variety of genetic aberrations, alterations in cellular metabolism have been implicated. Epidermal growth factor receptor (EGFR) is a cell surface protein that is frequently mutated in NSCLC. In this review, we discuss the effects of EGFR mutants on cell proliferative and survival signals, as well as metabolic reprogramming, in NSCLC. We also discuss the use and mechanisms of action of tyrosine kinase inhibitors (TKIs) that target EGFR-mutants and mediate their inhibitory effects by inducing cell death. Development of resistance to EGFR-TKIs is a problem in the clinic. We further discuss the approaches that are used to overcome this resistance, including the development of fourth-generation EGFR-TKIs. Immunotherapy is not very effective in EGFR-mutant NSCLC. We also discuss possible underlying mechanisms for the inadequate response of EGFR-mutant tumors to immunotherapeutics. Given that mutant EGFR transduces survival signals, and affects cellular metabolism, a better understanding of the crosstalk between mutant EGFR-mediated signals and metabolic reprogramming is expected to facilitate the development of newer personalized therapeutics to manage lung cancer.

Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.

Supplementary Tables S1-S4 from Neutral Sphingomyelinase-3 Is a DNA Damage and Nongenotoxic Stress-Regulated Gene That Is Deregulated in Human Malignancies

The use of antibody-drug conjugates is expected to transform the management of human malignancy. Antibody-drug conjugates for cancer treatment are designed to deliver anticancer drugs to tumor cells. The main components of such conjugates are a monoclonal antibody that binds to a tumor antigen, an anticancer drug to inhibit tumor cell growth and a linker that serves to conjugate the antibody and drug. The antibody-drug conjugates developed and approved for breast cancer treatment are ado-trastuzumab emtansine, (fam)-trastuzumab deruxtecan-nxki and sacituzumab govitecan. The mechanisms of action, clinical uses and toxic effects of these antibody-drug conjugates are discussed.

Supplementary Tables 1-3 from Cloning and Characterization of a p53 and DNA Damage Down-regulated Gene <i>PIQ</i> that Codes for a Novel Calmodulin-Binding IQ Motif Protein and Is Up-regulated in Gastrointestinal Cancers

Background : Breast cancer (BC) is a malignant neoplasm that arises from the uncontrolled growth and cell proliferation in the breast tissue. The BC is classified into various types defined by underlying molecular types such as estrogen receptor positive (ER+), progesterone receptor positive (PR+), human epidermal growth factor positive (HER2+) and triple negative (TN) breast cancer. Timely diagnosis of various distinct breast cancer types is crucial in the choice of an appropriate treatment strategy. Here we report the key genes and the use of machine learning (ML) approach for classification of TNBC and ER+ patients using gene expression data. Method : The RNA Sequencing data analysis was performed on TNand ER+ tumor samples from ENA to obtain differentially expressed genes. The DAVID database was used to conduct pathway enrichment analysis. There has been considerable enrichment of these differentially expressed genes (DEGs) in cancer-related functions and pathways. An interaction network between genes was then constructed using the STRING database. Lastly, we evaluated three different classification models including Support vector machine, k nearest neighbor and Naïve Bayes using different threshold levels to train the models for classifying two types of breast cancer. Results : DEG’s were obtained as a result of this study which can differentiate between ER+ and TNBC types. We filtered out 10 hub genes by cytohubba plug-in including CDC20, CDK1, BUB1, AURKA, CDCA8, RRM2, TTK, CENPF, CEP55 and NDC80 which can be used for the prognosis and can generate therapeutic alternatives. Among the three ML algorithms, kNNwas able to classify more accurately. Conclusion : 10 hub genes were identified which can be used to study the clinical and molecular behavior of breast cancer and to generate therapeutic alternatives to increase the survival rate and the prediction results of ML algorithm can be used to classify the breast cancer types.

Supplementary Tables 1-3 from Cloning and Characterization of a p53 and DNA Damage Down-regulated Gene <i>PIQ</i> that Codes for a Novel Calmodulin-Binding IQ Motif Protein and Is Up-regulated in Gastrointestinal Cancers

Research on Rab-like protein 1A (RBEL1A) in the past two decades highlighted the oncogenic properties of this gene. Despite the emerging evidence, its importance in cancer biology was underrated. This is the first RBEL1A critical review covering its discovery, biochemistry, physiological functions, and clinical insights. RBEL1A expression at the appropriate levels appears essential in normal cells and tissues to maintain chromosomal stability; however, its overexpression is linked to tumorigenesis. Furthermore, the upstream and downstream targets of the RBEL1A signaling pathways will be discussed. Mechanistically, RBEL1A promotes cell proliferation signals by enhancing the Erk1/2, Akt, c-Myc, and CDK pathways while blunting the apoptotic signals via inhibitions on p53, Rb, and caspase pathways. More importantly, this review covers the clinical relevance of RBEL1A in the cancer field, such as drug resistance and poor overall survival rate. Also, this review points out the bottle-necks of the RBEL1A research and its future research directions. It is becoming clear that RBEL1A could potentially serve as a valuable target of anticancer therapy. Genetic and pharmacological researches are expected to facilitate the identification and development of RBEL1A inhibitors as cancer therapeutics in the future, which could undoubtedly improve the management of human malignancy.

Sacituzumab govitecan is an antibody-drug conjugate. It is composed of a humanized monoclonal antibody raised against the trophoblast cell-surface antigen 2 (Trop-2), and linked to SN-38, which is an active metabolite of topoisomerase I inhibitor anticancer drug irinotecan. A hydrolyzable linker conjugates the antibody and the drug. Trop-2 is overexpressed in various tumors including the triple-negative breast cancers (TNBCs) that are more aggressive with limited therapeutic options. Sacituzumab govitecan has proven to be an important therapeutic modality to manage the TNBCs. It has shown progression-free survival (PFS) and overall survival (OS) benefits when compared to standard-of-care chemotherapeutics. Accordingly, it is approved for the treatment of TNBCs in the United States and the European Union. Sacituzumab govitecan has also shown PFS and OS benefits for hormone receptor-positive (HR+) and human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancers. Therefore, sacituzumab govitecan appears to be an option for HR+/HER2- metastatic breast cancers that are heavily pretreated and exhibit endocrine resistance. Although sacituzumab govitecan has shown promise, it also is toxic. Additional studies are therefore needed to further refine the use of sacituzumab govitecan in improving the management of metastatic breast cancer.

Supplementary Data from DOC45, a Novel DNA Damage–Regulated Nucleocytoplasmic ATPase That Is Overexpressed in Multiple Human Malignancies

PDF - 430K, Supplementary Fig. S1 UV Spectrum of Lappaol F Supplementary Fig. S2 1H NMR Spectrum of Lappaol F Supplementary Fig. S3 13C NMR Spectrum of Lappaol F. Supplementary Fig. S4 ESI MS Spectrum of Lappaol F Supplentary Fig S5 Purity of Lappaol F determined by HPLC Supplementary Fig. S6 Cytotoxic effect of Lappaol F on various tumor cell lines. Supplementary Fig. S7 p53 expression in MCF-7 and RKO cells with or without Lappaol F treatment.

The cyclin-dependent kinase (CDK) inhibitors have emerged as important cancer therapeutics. To date, three CDK4/6 inhibitors in combination with endocrine therapy have been approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. These include, palbociclib, ribociclib and abemaciclib. More recently, a newer CDK4/6 inhibitor named dalpiciclib has been tested in the phase III DAWNA-1 study, which is a randomized, double-blind, placebo-controlled trial that investigates dalpiciclib in combination with fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer patients that have relapsed or progressed on prior endocrine therapy. Dalpiciclib is an oral agent and an emerging ATP-competitive CDK4/6 inhibitor. The interim results of DAWNA-1 study revealed that dalpiciclib in combination with fulvestrant significantly prolonged the progression-free survival. The clinical use and side effects of palbociclib, ribociclib and abemaciclib as well as dalpiciclib are reviewed here.

Plants are major source for discovery and development of anticancer drugs. Several plant-based anticancer drugs are currently in clinical use. Fagonia indica is a plant of medicinal value in the South Asian countries. Using mass spectrometry and NMR spectroscopy, several compounds were purified from the F. indica extract. We have used one of the purified compounds quinovic acid (QA) and found that QA strongly suppressed the growth and viability of human breast and lung cancer cells. QA did not inhibit growth and viability of non-tumorigenic breast cells. QA mediated its anticancer effects by inducing cell death. QA-induced cell death was associated with biochemical features of apoptosis such as activation of caspases 3 and 8 as well as PARP cleavage. QA also upregulated mRNA and protein levels of death receptor 5 (DR5). Further investigation revealed that QA did not alter DR5 gene promoter activity, but enhanced DR5 mRNA and protein stabilities. DR5 is one of the major components of the extrinsic pathway of apoptosis. Accordingly, Apo2L/TRAIL, the DR5 ligand, potentiated the anticancer effects of QA. Our results indicate that QA mediates its anticancer effects, at least in part, by engaging DR5-depentent pathway to induce apoptosis. Based on our results, we propose that QA in combination with Apo2L/TRAIL can be further investigated as a novel therapeutic approach for breast and lung cancers.

We have previously reported that Monoglyceride Lipase (MGL) expression is absent or reduced in various human malignancies and MGL-deficient mice develop tumors in multiple organs. Evidence also suggests MGL to be a tumor suppressor, however, the mechanisms underlying its tumor-suppressive actions remain to be investigated. Here, we report a novel function of MGL as a negative regulator of XIAP, an important inhibitor of apoptosis. We found that MGL directly interacted with XIAP and enhanced E3-ligase activity and proteasomal degradation of XIAP. MGL overexpression induced cell death that was coupled with caspase activation and reduced XIAP levels. N-terminus of MGL was found to mediate interactions with XIAP and induce cell death. MGL-deficient cells exhibited elevated XIAP levels and exhibited resistance to anticancer drugs. XIAP expression was significantly elevated in tissues of MGL-deficient animals as well as human lung cancers exhibiting reduced MGL expression. Thus, MGL appears to mediate its tumor-suppressive actions by inhibiting XIAP to induce cell death.

Esophageal Cancer-Related Gene 2 (ECRG2) is a recently identified tumor suppressor, its regulation and involvement in DNA damage response are unknown. Here, we show that DNA damage-induced ECRG2 upregulation coincided with p53 activation and occurred in a p53-dependent manner. We identified two p53-binding sites within ECRG2 promoter and found the promoter activity, mRNA, and protein expression to be regulated by p53. We show that DNA damage significantly enhanced p53 binding to ECRG2 promoter at the anticipated p53-binding sites. We identified a novel natural ECRG2 promoter variant harboring a small deletion that exists in the genomes of ~38.5% of world population and showed this variant to be defective in responding to p53 and DNA-damage. ECRG2 overexpression induced cancer cell death; ECRG2 gene disruption enhanced cell survival following anticancer drug treatments even when p53 was induced. We showed that lower expression of ECRG2 in multiple human malignancies correlated with reduced disease-free survival in patients. Collectively, our novel findings indicate that ECRG2 is an important target of p53 during DNA damage-induced response and plays a critical role in influencing cancer cell sensitivity to DNA damage-inducing cancer therapeutics.

BACKGROUND:Recently, we have reported the characterization of a novel protein named Coiled-coil Helix Tumor and Metabolism 1 (CHTM1). CHTM1 localizes to both cytosol and mitochondria. Sequence corresponding to CHTM1 is also annotated in the database as CHCHD5. CHTM1 is deregulated in human breast and colon cancers and its deficiency in human cancer cells leads to defective lipid metabolism and poor growth under glucose/glutamine starvation.METHODS:Human cancer cell lines and tissue specimens were used. CHTM1 knockdown was done via lentiviral approach. CHTM1-expresssion constructs were developed and mutants were generated via site-directed mutagenesis approach. Western blotting, immunostaining, immunohistochemistry, cell fractionation and luciferase assays were performed. Reactive oxygen species and reactive nitrogen species were also measured.RESULTS:Here we report that CHTM1 deficiency sensitizes human lung cancer cells to metabolic stress-induced cell death mediated by glucose/glutamine deprivation and metformin treatment. CHTM1 interacts with Apoptosis Inducing Factor 1 (AIF1) that is one of the important death inducing molecules. CHTM1 appears to negatively regulate AIF1 by preventing AIF1 translocation to cytosol/nucleus and thereby inhibit AIF1-mediated caspase-independent cell death. Our results also indicate that p38, a stress kinase, plays a critical role in metabolic stress-induced cell death in CHTM1-deficient cells. Furthermore, p38 appears to enhance AIF1 translocation from mitochondria to cytosol particularly in metabolically stressed CHTM1-deficient cells and CHTM1 negatively regulates p38 kinase activity. The expression status of CHTM1 in lung cancer patient samples is also investigated and our results indicate that CHTM1 levels are increased in the majority of lung tumors when compared to their matching normal tissues.CONCLUSION:Thus, CHTM1 appears to be an important metabolic marker that regulates cancer cell survival under metabolic stress conditions, and has the potential to be developed as a predictive tumor marker.

Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric malignancies. Although it has shown promise as a biotherapeutic, its cardiotoxicity remains a major concern. Genotoxic anticancer anthracyclines such as doxorubicin and epirubicin are also known for their cardiotoxic effects. However, trastuzumab and anthracyclines are suggested to mediate cardiotoxicity via different pathways. The available lines of evidence suggest that trastuzumab can exacerbate the cardiotoxic effects of anthracyclines and thus, prior exposure to anthracyclines is regarded as one of the risk factors for trastuzumab-induced cardiotoxcity. Although it is generally believed that the trastuzumab-induced cardiotoxic effects are reversible, various preclinical studies have revealed its apoptotic effects on cardiomyocytes. Thus, the issue of the reversibility of its cardiotoxic effects remains to be fully resolved. This article discusses various mechanisms that have been proposed for the cardiotoxic effects of trastuzumab and the potential risk factors that can lead to cardiotoxicity. The recently approved anti-HER2 monoclonal antibodies including pertuzumab and ado-trastuzumab (T-DM1) are also discussed.