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Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

Background: Pancreatic ductal adenocarcinoma (PDAC), a difficult‐to‐treat cancer, is expected to become the second‐largest cause of cancer‐related deaths by 2030, while colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths. Currently, there is no effective treatment for PDAC patients. The development of novel agents to effectively treat these cancers remains an unmet clinical need. FL118, a novel anticancer small molecule, exhibits high efficacy against cancers; however, the direct biochemical target of FL118 is unknown. Methods: FL118 affinity purification, mass spectrometry, Nanosep centrifugal device and isothermal titration calorimetry were used for identifying and confirming FL118 binding to DDX5/p68 and its binding affinity. Immunoprecipitation (IP), western blots, real‐time reverse transcription PCR, gene silencing, overexpression (OE) and knockout (KO) were used for analysing gene/protein function and expression. Chromatin IP was used for analysing protein‐DNA interactions. The 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromid assay and human PDAC/CRC cell/tumour models were used for determining PDAC/CRC cell/tumour in vitro and in vivo growth. Results: We discovered that FL118 strongly binds to dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway without decreasing DDX5 mRNA. Silencing and OE of DDX5 indicated that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins, including survivin, Mcl‐1, XIAP, cIAP2, c‐Myc and mutant Kras. Genetic manipulation of DDX5 in PDAC cells affects tumour growth. PDAC cells with DDX5 KO are resistant to FL118 treatment. Our human tumour animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and CRC tumours that have a high expression of DDX5, while FL118 exhibits less effectiveness in PDAC and CRC tumours with low DDX5 expression. Conclusion: DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a 'molecular glue degrader' to directly glue DDX5 and ubiquitination regulators together to degrade DDX5. [ABSTRACT FROM AUTHOR]

Simple Summary: FL118 is a novel orally available small molecule anticancer drug. We found that bladder cancer cells with a mutant Kras is highly sensitive to FL118-induced cell growth inhibition and cell death induction through inhibiting the anti-cancer cell death and drug resistance factors (survivin, Mcl-1, XIAP). In the Kras-mutation bladder cancer cells, FL118 can stimulate the reactive oxygen species (ROS) over-production for killing bladder cancer cells and inhibiting bladder cancer cell-established tumor growth. Elimination of mutant Kras by Kras-specific shRNA technology in mutant Kras-containing bladder cancer cell-established tumor decreased FL118 effectiveness to inhibit bladder cancer tumor growth. In this regard, mutant Kras is a potential favorable biomarker for FL118. This finding is significant because mutant Kras is known to be a formidable challenge treatment resistant factor in various types of cancer. Thus, FL118 could use mutant Kras as favorable biomarker for patient selection to carry out precision medicine. Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment. [ABSTRACT FROM AUTHOR]

Highlights: [•] YY1 overexpression resulted in survivin promoter repression in a luciferase system. [•] YY1 knockdown using siRNA releases the survivin repression. [•] Using a YY1 tet-off system, YY1 expression represses survivin expression. [•] YY1 is capable of directly binding to the survivin promoter. [ABSTRACT FROM AUTHOR]

Abstract: Growing evidence suggests a role for the antiapoptotic protein survivin in promotion of cancer cell G1/S transition and proliferation. However, the underlying mechanism is unclear. Further, although upregulation of p21WAF1/CIP1 by p53 plays an important role in p53-mediated cell G1 arrests in response to various distresses, it is unknown whether survivin plays a role in the regulation of p21WAF1/CIP1 expression. Here, we report that exogenous expression of survivin in p53-wild type MCF-7 breast cancer cells inhibits the expression of p21WAF1/CIP1 protein, mRNA and promoter activity, while the survivin C84A mutant and antisense failed to do so. Cotransfection experiments in the p53 mutant H1650 lung cancer cell line showed that survivin neutralizes p53-induced p21WAF1/CIP1 expression and promoter activity. Importantly, genetically silencing of endogenous survivin using lentiviral survivin shRNA also enhances endogenous p21 in p53 wild type cancer cells, suggesting the physiological relevance of the fining. We further demonstrated that both p53 and survivin interacts on the two p53-binding sites in the p21WAF1/CIP1 promoter (−2313 to −2212; −1452 to −1310), and survivin physically interacts with p53 in cancer cells. Together, we propose that survivin may act as a transcription factor or cofactor to interact with p53 on the p21WAF1/CIP1 promoter leading to the inhibition of p21WAF1/CIP1 expression at least in part by neutralizing p53-mediated transcriptional activation of the p21 gene. [Copyright &y& Elsevier]