Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

“…Recent studies showed that targeting NDRG1 blocks the crosstalk between PC cells and matrix [ 83 ]. The TGF-β/Smad4 signaling axis plays an important role in regulating the TME and mediating tumor-stroma crosstalk [ 84 ]. The Met/HGF pathway not only involves the interaction between cancer cells and activated PSCs but also takes part in the crosstalk between tumor and matrix [ 85 ].…”

Molecular alterations in pancreatic tumors

“…Moreover, the survival period in these patients was significantly shorter when compared to those with a pancreatic tumor characterized by intact p16 functions[ 33 , 56 , 57 ]. CDK4/6 is a potential target in CDKN2A-deficient tumors and the efficacy of CDK4 inhibitors has been confirmed in PDAC preclinical models[ 58 ].…”

“…Different to solid pseudopapillary neoplasia (SPN), CTNNB1 mutations are uncommon in PDAC[ 15 , 71 ]. In PDAC, the frequency of NTRK (neurotrophic tropomyosin receptor kinase) fusion is very low (about 0.3%), but clinical trials revealed that the selective TRK (tropomyosin receptor kinase) inhibitors are also effective in PDAC harboring NTRK rearrangement[ 58 ]. NCCN guidelines suggest the use of a TRK inhibitor in NTRK gene fusion-positive advanced/metastatic pancreatic cancer[ 61 , 65 ].…”

Dissection of N-, O- and glycosphingolipid glycosylation changes in PaTu-S pancreatic adenocarcinoma cells upon TGF-β challenge

“…KRAS mutations occurs in the early stage of PDAC (5), whereas mutations of TP53 , SMAD4 , and CDKN2A arise in advanced pancreatic intraepithelial neoplasias and invasive pancreatic adenocarcinomas (6–8). These common genetic abnormalities can profoundly perturb protein interactions and specific signaling pathways related to cell survival (9, 10), DNA damage repair (11), angiogenesis (12, 13), invasion (14), metastasis (15) and immune responses (16, 17),…”