Role In Cancer Therapy Resistance Research Articles

Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies.

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

Protein tyrosine phosphatases: emerging role in cancer therapy resistance.

Tyrosine phosphorylation of intracellular proteins is a post-translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross-talk between signaling pathways. In the context of cancer, PTP-mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth-stimulatory signaling pathways or modulation of the immune-suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy. This review aimed to elaborate recent insights that supported the involvement of PTP-mediated pathways in the development of resistance to targeted therapy and immune-checkpoint therapy. This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long-term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced-stage tumors.

Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation

Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

EBV infection-induced GPX4 promotes chemoresistance and tumor progression in nasopharyngeal carcinoma

Epstein–Barr virus (EBV) was the first oncogenic virus identified in humans. It is primarily associated with multiple lymphoid and epithelial cancers, including nasopharyngeal carcinoma (NPC). However, its association with ferroptosis and its role in cancer therapy resistance have not been fully elucidated. Here, we show that EBV infection reduces the sensitivity of NPC cells to ferroptosis by activating the p62-Keap1-NRF2 signaling pathway in conjunction with upregulation of SLC7A11 and GPX4 expression. Knockdown of endogenous GPX4 or blockade of GPX4 using a specific inhibitor enhanced the chemosensitivity of EBV-infected NPC cells. Functional studies revealed that GPX4 knockdown suppresses the proliferation and colony formation of NPC cells. Mechanistically, GPX4 interacts with the TAK1-TAB1/TAB3 complex, regulates TAK1 kinase activity, and further activates downstream MAPK-JNK and NFκB pathways. High GPX4 expression is correlated with poor clinical outcomes in patients with NPC and other cancer types. Taken together, our findings suggest that EBV infection has important effects on redox homeostasis, revealing a previously unappreciated role for GPX4 in tumor progression. This novel mechanism provides a potential new target for the treatment of EBV-related tumors.

Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance.

The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.

Abstract LB-023: STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin

Abstract Cancer stem cells (CSCs) are considered to play an important role in cancer therapy resistance, metastasis, and recurrence. Wnt/β-catenin is one of key signaling pathways that confer cancer stemness properties to a portion of the heterogeneous cancer cell population. Dysregulation of the Wnt/β-catenin pathway may lead to accumulation of β-catenin and aberrant activation of its target gene transcription. However, it has been proven difficult to design a therapeutic targeting β-catenin. Identification of a drugguble target for the β-catenin pathway is highly desirable given the importance of β-catenin in promoting cancer stemness. Here, we demonstrate that Serine Threonine Kinase 17A (STK17A), a novel member of the death-associated protein family of serine/threonine kinases, promotes cancer stemness phenotypes via β-catenin. Over-expression of STK17A resulted in increased anchorage-independent spherogenesis and invasive phenotype of cancer cells, whereas STK17A gene silencing reduced these malignant phenotypes. Overexpression of STK17A led to increased transcriptional activity of β-catenin and upregulation of its target genes. These changes were accompanied by increased phosphorylation of β-catenin at ser675. Cell-free in vitro kinase assay revealed that STK17A directly phosphorylates β-catenin at ser675 in an ATP-dependent manner. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness kinase inhibitor, was found to potently inhibit STK17A, leading to inhibition of β-catenin phosphorylation at ser675. These results suggest that inhibition of STK17A is a promising approach for targeting cancer stemness. Citation Format: Taiki Kida, Harry A. Rogoff, Chiang J. Li. STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-023. doi:10.1158/1538-7445.AM2017-LB-023

How do tenascins influence the birth and life of a malignant cell?

Tenascins are large glycoproteins found in embryonic and adult extracellular matrices. Of the four family members, two have been shown to be overexpressed in the microenvironment of solid tumours: tenascin-C and tenascin-W. The regular presence of these proteins in tumours suggests a role in tumourigenesis, which has been investigated intensively for tenascin-C and recently for tenascin-W as well. In this review, we follow a malignant cell starting from its birth through its potential metastatic journey and describe how tenascin-C and tenascin-W contribute to these successive steps of tumourigenesis. We consider the importance of the mechanical aspect in tenascin signalling. Furthermore, we discuss studies describing tenascin-C as an important component of stem cell niches and present examples reporting its role in cancer therapy resistance.

GTP binding and growth control

Ras protein was discovered more than 30 years ago and since then extensive research in the area of ras biology has clearly established the diverse roles of this master regulator in cancer. Nevertheless, this knowledge could not be translated into the development of clinically viable therapeutic agents against ras. The primary reason is the lack of possible drug-binding pockets within the ras structure itself as well as its high affinity to GTP that does not allow easy access to small molecule drugs. Alternatively, researchers have focused on targeting the upstream [epidermal growth factor receptor, insulin-like growth factor 1 receptor (IGF1R)] and downstream signaling pathways [such as the rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase kinase (MEK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)] among others. However, none of these targets proved to be actionable and showed limited clinical benefits or often time acute toxicity in patients. Lack of response to downstream targets have been attributed to the diverse cross talk and feedback mechanisms in ras signaling and such attempts are yet to yield any clinically viable candidate molecules. Over the last decade the small GTPases such as Rho, Rac, and CDC42 have also been explored as potential therapeutic targets within the mutant ras signaling. The p21 activated kinases (PAKs) Rho GTPase effectors that are emerging to play a key role in cancer therapy resistance and stemness. There are two groups of PAKs [group I PAKs (1, 2, and 3) and group II PAKs (4, 5, and 6)]. This chapter highlights the multi-faceted roles of PAKs in cancer signaling and also brings forward some of the recent attempts to target key players particularly belonging to the group II kinases.