Advances and challenges in targeted therapy for colorectal cancer: A focus on adenomatous polyposis coli and kirsten rat sarcoma virus mutations
image: APC, adenomatous polyposis coli; CBP, cAMP-response element binding protein; CIBP, calcium- and integrin-binding protein; CK, creatine kinase. CtBP, C-terminal binding protein; GRO, growth-regulated oncogene alpha; GSK, glycogen synthase kinase LRP5/6, low-density lipoprotein receptor-related protein (LRP)5 and 6; Tcf/Lef, T-cell factor/lymphoid enhancer factor.
Credit: Guo-Qing Chen, Si-Bao Chen, Rui-Hong Gong
Colorectal cancer (CRC) remains a significant global health challenge, with substantial regional variations in incidence and marked gender differences. The disease's complexity is driven by intricate molecular signaling pathways involving multiple gene mutations, notably in the adenomatous polyposis coli (APC) and Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) genes. These mutations are crucial in the development and progression of CRC, making them focal points in current research aimed at developing effective targeted therapies. Despite advancements, the translation of these insights into clinical treatments faces significant hurdles, particularly due to the heterogeneity of CRC and the emergence of drug resistance.
APC Mutations in CRC
APC, a tumor suppressor gene, is frequently mutated in CRC, occurring in 70-80% of cases. This gene plays a central role in the Wnt/beta-catenin signaling pathway, regulating the proliferation and differentiation of gastrointestinal cells. APC mutations disrupt this pathway, leading to uncontrolled cell growth and tumorigenesis. The gene’s importance is underscored by the fact that most of its mutations occur within a specific region, exon 15, which encodes a significant portion of the protein responsible for inhibiting beta-catenin-mediated transcription. Restoring APC function has shown promise in preclinical studies, indicating that targeting the Wnt pathway could be a viable therapeutic strategy.
KRAS Mutations in CRC
KRAS is another critical gene frequently mutated in CRC, found in 30-50% of cases. The gene encodes a protein that plays a vital role in several signaling pathways, including the RAS-RAF-MAPK and PI3K-Akt pathways, which are essential for cell proliferation and survival. Mutations in KRAS lead to the continuous activation of these pathways, promoting cancer cell growth and resistance to therapies targeting the epidermal growth factor receptor (EGFR). KRAS mutations are associated with poorer prognoses, particularly those in codons 12 and 13, which are linked to more aggressive cancer phenotypes and reduced survival rates.
Clinical Challenges
The current treatment landscape for CRC includes surgery, chemotherapy, and targeted agents. However, the effectiveness of these therapies is often limited by the genetic heterogeneity of CRC and the development of drug resistance. Targeted therapies specifically aimed at APC and KRAS mutations have yet to receive FDA approval, primarily due to the complexity of these pathways and the challenges in effectively targeting them. Drugs targeting the APC/Wnt/beta-catenin pathway are still in the preclinical or early clinical trial phases, and those targeting KRAS face significant obstacles due to the protein’s structure and the limited availability of binding sites for inhibitors.
Development of Novel Drug Combinations for CRC Treatment
Combination therapy has emerged as a promising approach to overcome the limitations of single-drug treatments. By targeting multiple pathways simultaneously, combination therapies can reduce the risk of drug resistance and improve treatment efficacy. This strategy is particularly important in CRC, where tumor heterogeneity is a significant challenge. The success of combination therapies in other cancers has spurred ongoing research into similar approaches for CRC, with the goal of developing treatments that can effectively target the complex and multifaceted nature of the disease.
Conclusions
While significant progress has been made in understanding the molecular mechanisms of CRC and developing targeted therapies, translating these insights into effective clinical treatments remains challenging. The development of combination therapies offers hope for improving patient outcomes by addressing the complexity and heterogeneity of CRC. Continued research into the genetic and molecular underpinnings of CRC, as well as the development of novel therapeutic strategies, is essential for advancing the treatment of this prevalent and deadly disease.
This expanded essay maintains the structure of the original review, incorporating the main sections and highlighting the critical research findings and challenges associated with APC and KRAS mutations in colorectal cancer.
Full text
https://www.xiahepublishing.com/2994-8754/JTG-2023-00063
The study was recently published in the Journal of Translational Gastroenterology.
Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.
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