WEE1 kinase inhibition to overcome acquired resistance to targeted therapies in colorectal cancer

Racism Is a Modifiable Risk Factor: Relationships Among Race, Ethnicity, and Colorectal Cancer Outcomes

Context: Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. Its progression is influenced by various molecular factors, including the dysregulation of microRNAs (miRNAs). MiR-373 is an oncogenic miRNA implicated in the development of CRC, but its precise role in tumor progression and metastasis remains under investigation. Objectives: This review aims to evaluate the role of miR-373 in CRC progression, focusing on its impact on key cellular processes such as proliferation, migration, and invasion. Additionally, the review explores the potential of miR-373 as a prognostic biomarker and therapeutic target in CRC. Methods: A systematic search was conducted using databases such as PubMed, Scopus, and Google Scholar to identify studies published from 2000 to 2025. The review includes studies that investigate miR-373 expression, its regulation of tumor suppressor genes, and its involvement in oncogenic signaling pathways, particularly those linked to CRC progression. Results: MiR-373 is often overexpressed in CRC tissues, promoting tumor growth by regulating critical cellular processes. It suppresses tumor suppressor genes like PTEN and TP53INP1, resulting in uncontrolled cell proliferation, reduced apoptosis, and enhanced invasion. Higher miR-373 levels are associated with advanced disease stages, metastasis, and poor clinical outcomes, suggesting its potential as a prognostic marker and therapeutic target. Conclusions: MiR-373 contributes significantly to CRC development and progression. Its upregulation is linked to increased tumor aggressiveness, metastasis, and resistance to therapy, making it a promising candidate for early detection and targeted therapies in CRC. Further studies should focus on modulating miR-373 expression to improve clinical outcomes.

Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.

Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancements in the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approaches like gene silencing techniques. Challenges such as nonspecificity, adverse side effects, and resistance mechanisms are discussed. We explore the potential of gelatinase inhibition in combination therapies, particularly with conventional chemotherapy and emerging targeted treatments, to enhance therapeutic efficacy and overcome resistance. The novelty of this review lies in its integration of recent findings on diverse inhibition strategies with insights into their clinical relevance, offering a roadmap for future research. By addressing the limitations of current approaches and proposing novel strategies, this review underscores the potential of gelatinase inhibitors in CRC prevention and therapy, inspiring further exploration in this promising area of oncological treatment.

As one of the most common malignancies, colorectal cancer (CRC) usually starts with a benign lesion and accumulates DNA damage as it progresses to full-fledged cancer. Glycyrrhizin (GL) has been found to alleviate tumor growth and inflammation, while the role of GL influences DNA damage response (DDR) in colorectal cancer remains unclear. GL exposure significantly reduced cell colony formation and viability with a concomitant increase in DNA fragmentation in CRC, meanwhile GL induced apoptosis by activating caspase-3. Moreover, GL induced cell cycle arrest in CRC cells at S phase, which was associated with decreased cyclin D1 in vitro. GL treatment significantly ameliorated tumor growth and promoted DDR in vivo. Mechanism analysis revealed that GL significantly downregulated the NHEJ pathway via inhibiting HMGB1. Finally, the expression of HMGB1 was abnormal regulated in CRC tissue than in adjacent normal tissues and associated with TNM stage and overall survival. Our findings indicate that HMGB1 may be a novel therapeutic target in CRC, a result that GL may serve as a promising drug for CRC treatment.

Background: Aberrant lipid metabolism is associated with poor prognosis in colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of lipogenesis, is overexpressed and a therapeutic target in CRC. Overexpression of CD36, a fatty acid translocase, plays a pro-tumorigenic role in CRC. BRAFV600E is the mutation occurring in about 10-15% of CRC cases. BRAF-targeted therapy is effective, but quickly developed resistance is an issue. Our preliminary data show that development of resistance to BRAF-targeted therapy is associated with an increase in expression of FASN, CD36, accumulation of triglycerides (TGs), and mitochondrial respiration. Therefore, our central hypothesis is that inhibition of lipid metabolism will sensitize CRC cells to BRAF inhibitors and overcome acquired resistance. Methods: We established HT29 cells and primary PT130 and PT2449pt cells resistant to PLX8394, a novel BRAF inhibitor. IC50 curves, PrestoBlue viability, CytoSelect™ 24-Well Cell Invasion, and Triglyceride Assays, Seahorse XF analysis, western blot, and confocal microscopy were used to evaluate differences between parental and resistant cells. RNA-seq and lipid analysis were used to evaluate changes in gene expression and lipids levels. Combination of PLX8394 and TVB3664 (FASN inhibitor) was tested on cell viability in parental and resistant cells. Results: PLX8394 resistant cells have a higher IC50, an increased proliferation, and invasion compared to parental cells. An increase in invasion of resistant cells is associated with a decrease in E-cadherin. RNA sequencing shows a significant increase in FASN expression. Western blot on resistant cells confirms upregulation of FASN, CD36, and other lipogenic markers. Consistently, resistant cells have an increase in levels of triglycerides as compared to parental cells. Seahorse XF Cell Mito Stress Test shows that resistant cells forgo the Warburg effect and instead rely more heavily on oxidative phosphorylation. To further support our hypothesis, FASN shRNA knockdown of FASN in parental HT29 cells is more susceptible to PLX8394 treatment compared to control. We also observed the synergetic effect of PLX8394 and TVB3664 treatment on cell viability in parental cells, but not in resistant cells. Conclusion: Our study demonstrates that resistance to BRAF inhibitors is associated with a significant increase in proliferation, metastasis, and upregulation of lipid metabolism. We show that combination of FASN and BRAF inhibitors has a combinational effect on inhibiting cell viability in parental but not resistant cells, suggesting that the addition of FASN inhibitor to the standard regimen for BRAFV600E mutation positive patients can improve efficacy of these therapies. Additional screening of lipid metabolism-targeted therapies in combination with standard BRAF regimens are needed to develop novel and more efficacious strategies for CRC patients with BRAF mutations. Citation Format: Mariah E. Geisen, Dang he, Chi Wang, Jill M. Kolesar, Yekaterina Zaytseva. Targeting lipid metabolism to improve efficacy of braf-targeted therapy in colorectal cancer [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 414.

CDK10 is a novel and relatively poorly characterized member of the CDC2 family of kinases. CDK10 has been reported to be involved in the regulation of the G2/M phase of the cell cycle. Its role in cancer is unclear. A meta-analysis of gene expression profiling studies has consistently demonstrated higher expression of this protein in colorectal cancer (CRC) but its role is unknown. In this study, we were interested in examining the role of CDK10 in growth, apoptosis, chemoresistance, and as a therapeutic target in CRC. CRC cell lines stably overexpressing CDK10 wild type (WT) as well as a kinase defective/dominant negative (DN) form of CDK10 were established in CRC cell lines RKO, HCT-15 and MIP101. Knockdown of CDK10 was achieved via siRNA. MTS and colony-forming assays were used to examine the response to 5-Fluorouracil (5-FU); TUNEL, caspase 3/7 assays, for apoptosis; and signaling events by immunoblotting. Cell growth in vivo was monitored after injection of cell lines into the flanks of Nude mice. To examine CDK10's role as a potential target, SCID mice implanted SC with patient-derived CRC were injected with lentiviral siRNA targeting CDK10 and tumor growth was examined. Overexpression of CDK10 WT in RKO cells resulted in greater in vitro cell proliferation in comparison to either the DN or the control cells. It also inhibited apoptosis by 32%, while overexpression of the CDK10 DN protein was associated with an augmentation of apoptosis (>50%). Knockdown of CDK10 via siRNA confirmed a significant decrease in cell viability (20-60%) and a significant increase in apoptosis (>80%). This was associated with a downregulation of Bcl-2 and Bcl-xL expression. Interestingly, inhibition of apoptosis in CDK10 WT RKO cells could be achieved by inhibiting the expression of Bcl-2 and Bcl-xL by siRNA. The sensitivity of CRC cells to 5-FU was also dramatically reduced in cells overexpressing CDK10, as demonstrated by the significant higher IC50 in these cells. Colony-forming assay showed involvement of the kinase activity in 5-FU resistance since CDK10 DN HCT-15 cells displayed higher sensitivity and the CDK10 WT HCT-15 higher resistance to 5-FU. In line with the in vitro results, in vivo studies revealed that HCT-15 tumor xenografts expressing CDK10 WT have a significantly greater rate of growth than tumors expressing basal levels of CDK10. Interestingly, tumors of CDK10 DN cells had the slowest rate of growth. Furthermore, in vivo knockdown of CDK10 significantly impaired the growth of human SC implanted CRC tumors, as compared to control, with a ΔT/ΔC close to 0% by 26 days of treatment. CDK10 appears to be involved in the pathogenesis of CRC by influencing cell growth, apoptosis and chemotherapy resistance, in part, through its kinase active site. In addition, in vivo results using patient-derived tumors showed a significant reduction in tumor growth, following siRNA knockdown of CDK10, thereby demonstrating it to be a potential target for therapy in CRC. Citation Format: Louis-Bastien Weiswald, Mohammad R. Hasan, Mahbuba Rahman, Clarissa Pasiliao, Isabella T. Tai. CDK10 promotes tumour growth and chemoresistance in colorectal cancer, and is a potential target for treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2047. doi:10.1158/1538-7445.AM2015-2047

The aim of the present study was to investigate the effect of the actin‑binding protein Girdin on the proliferation, invasion and migration of colorectal cancer (CRC) cells. Cultured CRC cells (LoVo cell line) were transfected by Girdin‑specific and control shRNA constructs and analyzed for proliferation, invasion and migration by the MTT, Transwell and wound‑healing assays, respectively. The activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and expression of proinflammatory cytokines was examined by western blotting and ELISA assay, respectively. The effect of Girdin silencing on CRC growth was also evaluated in a xenograft model using nude mice, which were subcutaneously injected with Girdin‑deficient and negative control LoVo cells and analyzed for tumor volume and weight. Transfection of LoVo cells with Girdin‑specific shRNA inhibited Girdin mRNA expression to 27.5% and protein expression to 36.7% when compared with expression levels in the control cells (P<0.001) and significantly demonstrated suppression of LoVo cell proliferation (P<0.05), invasion (P<0.01) and migration (P<0.01). Furthermore, Girdin silencing downregulated the phosphorylation of the signaling proteins JAK (by 42%, P<0.001) and STAT3 (by 34%, P<0.01) and the content of IFN (by 28%, P<0.001) and IL‑6 (by 44%, P<0.001) compared to the control. Notably, inhibition of Girdin expression effectively suppressed tumorigenicity of LoVo cells invivo as evidenced by the reduced volume (P<0.05) and weight (P<0.05) of the tumors derived from Girdin shRNA‑transfected LoVo cells compared to those from the control cells. In conclusion, the silencing of Girdin expression inhibited the malignant behavior of CRC cells via the downregulation of the JAK/STAT signaling pathway, indicating Girdin as a potential therapeutic target in CRC. In the present study, we revealed, for the first time, that the malignant behavior of CRC cells depended on the expression of an actin‑binding protein, Girdin. Silencing of Girdin expression by specific shRNA suppressed the proliferation, invasion, and migration of CRC cells through the decrease in proinflammatory cytokines IFN and IL‑6 and the downregulation of the JAK/STAT signaling pathway. Our findings indicated that Girdin expression may be a potential novel therapeutic target in CRC.

Biological Implications and Clinical Potential of Metastasis-Related miRNA in Colorectal Cancer

RNA-binding proteins (RBPs) play critical roles in regulating post-transcriptional gene expression, managing processes such as mRNA splicing, stability, and translation. In normal intestine, RBPs maintain the tissue homeostasis, but when dysregulated, they can drive colorectal cancer (CRC) development and progression. Understanding the molecular mechanisms behind CRC is vital for developing novel therapeutic strategies, and RBPs are emerging as key players in this area. This review highlights the roles of several RBPs, including LIN28, IGF2BP1–3, Musashi, HuR, and CELF1, in CRC. These RBPs regulate key oncogenes and tumor suppressor genes by influencing mRNA stability and translation. While targeting RBPs poses challenges due to their complex interactions with mRNAs, recent advances in drug discovery have identified small molecule inhibitors that disrupt these interactions. These inhibitors, which target LIN28, IGF2BPs, Musashi, CELF1, and HuR, have shown promising results in preclinical studies. Their ability to modulate RBP activity presents a new therapeutic avenue for treating CRC. In conclusion, RBPs offer significant potential as therapeutic targets in CRC. Although technical challenges remain, ongoing research into the molecular mechanisms of RBPs and the development of selective, potent, and bioavailable inhibitors should lead to more effective treatments and improved outcomes in CRC.

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and the second leading cause of cancer-related deaths in developed countries, with the majority of deaths being attributed to distant metastasis. Therefore, it is necessary to identify a novel biomarker for cancer progression and metastasis, one that could also be a useful therapeutic target in CRC. Amplification of chromosome 7p is frequent in CRC, and it has been considered to harbor driver genes that promote tumorigenesis or tumor progression by the gain of function. We aimed to identify novel candidate driver genes on chromosome 7p and to clarify the clinical significance of their expression in CRC. Material and Methods: 1. We selected the candidate genes that satisfied the following criteria using CRC data from The Cancer Genome Atlas (TCGA). 1) The DNA copy number and mRNA expression are positively correlated with each other, 2) overexpressed in the tumor tissues compared to the normal tissues. 2. The mRNA expression of the candidate genes was measured in 147 surgically-resected CRC tissues and the paired normal tissues in our hospital by quantitative RT-PCR. The differences of mRNA expression between CRC tissues and normal tissues were analyzed by Mann Whitney U-test. 3. Survival analysis between high and low expression group of the candidate genes was performed by the Kaplan-Meier method. Correlation between the mRNA expression of the candidate genes and the clinicopathological factors were analyzed by Fisher’s exact test. 4. Gene Set Enrichment Analysis (GSEA) was performed in CRC data from TCGA to clarify the correlation between the candidate genes and gene sets that are associated with tumorigenesis or tumor progression. Results: The Golgi to ER traffic protein 4 (GET4) was identified as a candidate driver gene. GET4 is known to be one factor of the BCL2-associated athanogene 6 (BAG6) chaperone complex and function as a regulator for the nucleo-cytoplasmic transport of BAG6. The BAG6 complex is implicated in diverse cellular processes including apoptosis, co-chaperone, and DNA damage response. The expression of GET4 was significantly higher in CRC tissues than in normal colon tissues (p=0.03), and it correlated with depth invasion (p=0.02), and lymphatic invasion (p=0.01). The high GET4 expression group had a significantly poorer prognosis than the low expression group (p=0.02). On multivariate analysis, distant metastasis was an independent prognostic factor affecting OS (p&amp;lt;0.05) with hazard ratios (95% CI) of 66.6 (5.46-1649.3) among clinicopathological factors. GSEA showed that GET4 expression was negatively correlated with the pathway associated with the Rb-related protein p130, which belongs to the RB gene family proved to be a tumor suppressor. Conclusions: GET4 could be a promising driver gene of CRC on chromosome 7p possibly through regulating the location of BAG6. GET4 may be a therapeutic target as well as a poor prognostic biomarker in CRC. Note: This abstract was not presented at the meeting. Citation Format: Kensuke Koike, Takaaki Masuda, Kuniaki Sato, Yuushi Motomura, Jyunnichi Takahashi, Dai Shimizu, Shotaro Kuramitsu, Atsushi Fujii, Akihiro Kitagawa, Miwa Noda, Yusuke tsuruda, Hajime Ootu, Yousuke Kuroda, Hidetoshi Eguchi, Takashi Nakagawa, Koushi Mimori. Clinical significance of GET4 expression in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5238.

Background Colorectal cancer (CRC) outcomes remain limited through resistance to fluoropyrimidine-based therapy. Human equilibrative nucleoside transporter 1 (hENT1) regulates nucleoside analogue uptake and may drive chemoresistance through altered expression. To date, its role in CRC remains poorly defined. Methods Paired tumour and normal tissues from a clinical CRC cohort were analysed for hENT1 expression and correlation with outcome. Results were then validated using public transcriptomic datasets. CRC cell lines were profiled at transcriptomic and proteomic levels, and selective lentiviral knockdown models were established and validated. Functional assays assessed proliferation, cell adhesion and barrier function, and sensitivity to 5-FU and capecitabine, with and without pharmacological hENT1 inhibition. Results High hENT1 expression correlated with adverse survival outcomes, including reduced disease-free and metastasis-free survival, findings reproduced in external datasets. In vitro, validated hENT1 knockdown reduced proliferative capacity and demonstrated impaired adhesion and spreading, consistent with cellular stress. Functionally, hENT1 knockdown increased sensitivity to both 5-FU and capecitabine. Pharmacological inhibition with NBMPR further enhanced cytotoxicity in both wildtype and knockdown cells, confirming that hENT1 activity directly modulates fluoropyrimidine response. Conclusions hENT1 functions as both a prognostic and predictive biomarker in CRC. Functional data demonstrate that knockdown reduces proliferation and adhesion while sensitising cells to fluoropyrimidines, with pharmacological inhibition producing the greatest enhancement of efficacy. These findings highlight hENT1's potential as a prognostic biomarker and a translational therapeutic target in CRC.

Colorectal cancer (CRC) is one of the most frequently diagnosed malignant diseases worldwide and occurs at an alarmingly increasing rate especially in young adults. Ongoing progress in the field of cancer pharmacology has provided new treatment options in recent years, particularly in the form of immunotherapy. Yet, standard chemotherapy has been based on cytostatic agent 5‐fluorouracil (5‐FU) for over five decades with the more recent addition of leucovorin (LV), oxaliplatin (OXA) and irinotecan (IT). Established chemotherapeutic approaches mainly rely on the induction of DNA damage, which particularly affects rapidly growing cancer cells. The altered tumor metabolism and the DNA repair machinery have more recently been identified as potential drug targets in CRC. The assessment of novel anticancer drugs for CRC with a focus on induction of DNA damage, inhibition of DNA repair and disruption of mitochondrial metabolism as potential mechanisms constituted the objective of this work. For this purpose, this PhD thesis aimed to evaluate the applicability of antitumor agents which are already clinically used in the treatment of other cancer entities, including the metabolic inhibitor devimistat and the poly (ADP‐ribose)‐polymerase inhibitors (PARPi) olaparib and veliparib. In addition, the biological activity of novel chemical compounds for CRC treatment was analyzed. The investigated substances were either derived from natural sources (merosesquiterpenes isolated from marine sponges) or chemically synthesized as potential PARPi. CRC cell lines with varying mutational status were applied as surrogates representing the diversity of this disease and experiments with transient genetic knockdown or isogenic knockout cell lines were performed to further detail the pharmacological mode of action of the tested compounds. In addition, murine intestinal tumor organoids and primary organoids as well as patient‐derived short‐term cultures were used to elucidate the tumor cell specificity of the observed effects. An array of methods was utilized to investigate the underlying cell death mechanisms, including flow cytometry, confocal microscopy, western blot and gene expression analysis. The cytotoxicity of the mitochondrial disruptor devimistat and of PARPi in combination with established CRC chemotherapeutic 5‐FU, OXA and IT was analyzed in CRC cell lines to identify a potential synergy. Finally, devimistat was applied either as monotreatment or in combination with IT in a murine xenograft model to evaluate the therapeutic efficacy in vivo. At first, the tumor cell specific cytotoxicity of the metabolic inhibition by devimistat was revealed, independent of genetic and epigenetic alterations in CRC cell lines and murine tumor organoids. A reduced oxygen consumption rate (OCR), attenuated mitochondrial activity and induction of reactive oxygen species (ROS) were identified as underlying mechanisms, resulting in p53‐independent induction of CRC cell death. Synergistic anticancer activity was achieved by combination treatment with the chemotherapeutic agents IT and 5‐FU, as demonstrated by a Combenefit‐model and Chou‐Talalay analyses. Mechanistically, synergism was based on downregulation of antiapoptotic Bcl‐2 proteins and posttranslational accumulation of the proapoptotic protein Bim, as demonstrated by transient genetic knockout experiments. Antitumor efficacy and synergistic activity with IT were confirmed by applying human CRC cells in a xenograft mouse model. In the second study, a compound library comprised of 11 merosesquiterpenes isolated from marine sponges was analyzed and ilimaquinone (IQ), dactylospontriol (DS) and smenospongine (SP) were identified as the most cytotoxic compounds in a panel of three human CRC cell lines. On the mechanistic level, all three compounds induced DNA strand breaks and upregulated the DNA damage response (DDR) irrespective of the mutational status of p53, resulting in cell cycle arrest and activation of the mitochondrial apoptosis pathway. Furthermore, merosesquiterpenes induced pronounced cytotoxicity in murine intestinal tumor organoids, underlining their potential in CRC treatment. In the third study, the applicability of established and novel PARPi in the treatment of DNA repair deficient and proficient CRC was investigated. Therefore, the two novel compounds X17613 and X17618, which inhibit PARP‐1 activity in sub‐micromolar concentrations, were identified based on an in silico and in vitro screening of a library of novel 3,4bifunctionalized and ‐bridged indole compounds. In contrast to clinically applied PARPi olaparib and veliparib, both compounds showed no cytotoxicity in PARP‐1‐deficient and ‐proficient CRC cell line pairs. In accordance, absence of үH2AX formation and low PARP‐1 trapping activity compared to olaparib were identified after treatment with X17613 and X17618. In the last step, sensitization of BRCA2 (breast cancer type 2 susceptibility protein)‐deficient CRC cells to IT was demonstrated for X17613. In conclusion, our research assessed the potential of novel therapeutic approaches for CRC treatment, including mitochondrial disruption by the clinically applied metabolic inhibitor devimistat, inhibition of DNA repair by novel PARP‐1 inhibitors and DNA damage induction by marine sponge toxins. Our results provide insight into the underlying molecular mechanisms, the potential synergistic activity with clinically applied drugs and the impact of common CRC mutations on sensitivity to guide further development of new therapeutic approaches.

The aberrant expression of S100A11 has been identified in various malignancies but its functional roles and underlying mechanisms in colorectal cancer (CRC) have not been fully elucidated. Therefore, this study was designed to investigate the expression of S100A11 and its functional significance in CRC, indicating that S100A11 is significantly upregulated and correlates with poor survival outcomes in CRC. Functionally, S100A11 knockdown in CRC cell lines inhibited cell proliferation, invasion, and migration, leading to decreased tumour growth and metastasis in vivo. Mechanistic investigations revealed that S100A11 promotes cell proliferation and invasion by suppressing cell senescence. In addition, USP14 interacts with and mediates S100A11 deubiquitination. More importantly, the overexpression of S100A11 was able to partially counteract the reduction in cell proliferation caused by the knockdown of USP14. In summary, the novel regulatory axis involving USP14 and S100A11 modulates the malignant biological behavior of CRC cells through inhibiting cell senescence, therefore the interaction between USP14 and S100A11 represents a promising therapeutic target in CRC.

LncRNAs in colorectal cancer: Biomarkers to therapeutic targets