Abstract
Cancer is a devastating disease that claims over 8 million lives each year. Understanding the molecular etiology of the disease is critical to identify and develop new therapeutic strategies and targets. Chromosome instability (CIN) is an abnormal phenotype, characterized by progressive numerical and/or structural chromosomal changes, which is observed in virtually all cancer types. CIN generates intratumoral heterogeneity, drives cancer development, and promotes metastatic progression, and thus, it is associated with highly aggressive, drug-resistant tumors and poor patient prognosis. As CIN is observed in both primary and metastatic lesions, innovative strategies that exploit CIN may offer therapeutic benefits and better outcomes for cancer patients. Unfortunately, exploiting CIN remains a significant challenge, as the aberrant mechanisms driving CIN and their causative roles in cancer have yet to be fully elucidated. The development and utilization of CIN-exploiting therapies is further complicated by the associated risks for off-target effects and secondary cancers. Accordingly, this review will assess the strengths and limitations of current CIN-exploiting therapies, and discuss emerging strategies designed to overcome these challenges to improve outcomes and survival for patients diagnosed with cancer.
Highlights
Cancer is a significant global concern with more than 14 million new diagnoses and 8 million deaths attributed to this disease each year [1]
These results suggest that metabolic reprogramming, a hallmark of cancer cells [7], may represent a future broad-spectrum therapeutic target for cancers that exhibit Chromosome instability (CIN)
CIN-exploiting therapies represent an innovative strategy with great therapeutic potential and broad-spectrum applicability for cancer patients
Summary
Cancer is a significant global concern with more than 14 million new diagnoses and 8 million deaths attributed to this disease each year [1]. Colorectal cancer is the second leading cause of cancer-related deaths in the United States, and despite increased screening efforts, 21% of patients are initially diagnosed with metastases [4], while ~50% will inevitably develop metastatic disease [5]. CIN promotes oncogenesis by increasing the rate at which key genes—including oncogenes, tumor suppressor genes, DNA repair genes, and apoptotic genes—are gained, lost, or altered [24]. A precision medicine strategy that selectively exploits the aberrant genes (CIN genes) or pathways causing CIN would be effective in a myriad of cancers (at both primary and metastatic sites), and would reduce and/or eliminate many of the off-target side effects associated with many current chemotherapeutics [28,31,32,33]. We will present the relationship between CIN and cancer, discuss current and emerging therapeutic strategies that exploit CIN, and focus on the concerns and potential solutions for their effective clinical use
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