Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-offunction mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.

Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression

“…Pancreatic tumorigenesis results from the dysregulation of several core pathways and a myriad of genomic alterations [11]. Human pancreatic cancers have a specific mutational signature that include near-ubiquitous activating mutations of the oncogene KRAS (K Rat Sarcoma virus) and the frequent inactivation of the tumor suppressors TP53 (Tumor Protein P53), SMAD4/DPC4 (SMAD family Member4/Deleted in Pacreatic Carcinoma 4) e CDKN2A (Cyclin-Dependent KiNase inhibitor 2A) [12]. In general, KRAS mutations occur in stage 1 lesions (PanIN-1) and favor the initiation process; in PanIN-2, CDKN2A mutations emerge to induce further progression, while in stage 3 lesions (PanIN-3) and in invasive tumors, mutations of TP53 and SMAD4 drive the proliferation and expansion of cancer [12,13].…”

RelA Is an Essential Target for Enhancing Cellular Responses to the DNA Repair/Ref-1 Redox Signaling Protein and Restoring Perturbated Cellular Redox Homeostasis in Mouse PDAC Cells

“…Kras mutation is the most dominant oncogenic transformation in PDAC mutational profile confirmed in ∼90% of cases ( 2 ). The oncogenic Kras mutation leads to alteration of signaling pathways that are associated with the progression and metastasis of PDAC and is the main contributor of therapy recalcitrance ( 3 ).…”

Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets

“…The schema represents the development of PDAC from pancreatic intraepithelial neoplasia (PanIN) 1, 2, and 3 in the precancer stages. Clinical sequencing results indicate the mutation frequencies of KRAS (99%), TP53 (85%), and SMAD4 (55%) and telomere shortening (91%), although numerous additional mutations occur during the metastatic process 59 60,61 but recent studies have shown that cancer metabolism alterations such as phosphatidylinositol‐3 kinase (PI3K), AKT, mammalian target of rapamycin (mTOR), and sirtuins are supposed to be involved at least from PanIN 2 stages and can elicit oxidative stress and damage responses associated with genomic instability 62,63 .…”

“…Clinical sequencing results indicate the mutation frequencies of KRAS (99%), TP53 (85%), and SMAD4 (55%) and telomere shortening (91%), although numerous additional mutations occur during the metastatic process. 59 Tissue abnormality has been associated with hypoxia and the Warburg effect at early and advanced stages of pancreatic carcinogenesis, 60 , 61 but recent studies have shown that cancer metabolism alterations such as phosphatidylinositol‐3 kinase (PI3K), AKT, mammalian target of rapamycin (mTOR), and sirtuins are supposed to be involved at least from PanIN 2 stages and can elicit oxidative stress and damage responses associated with genomic instability. 62 , 63 Such alterations may induce further mutations in advanced stages of PDAC.…”