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-of-function 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.

Keywords: CDKN2A; KRAS; SMAD4; TP53; clinical implication; pancreatic cancer.

Fig. 1. Mutation profile of pancreatic cancer in the TCGA dataset.

Mutation information on 178 pancreatic cancers in the TCGA dataset was analyzed. KRAS/CDKN2A/TP53/SMAD4 are the most commonly mutated genes in pancreatic cancer, with mutation rates of 77%, 63%, 22%, and 16%, respectively. In addition, missense mutations and nonsense mutations are the main alteration types.

Fig. 2. Classical progression model of pancreatic cancer.

Pancreatic cancer is considered a disease of multiple genetic alterations, and mutations in KRAS/CDKN2A/TP53/SMAD4 promote the initiation and progression of precursor lesions. KRAS mutations occur in the early stage of PanIN-1; the loss of cdkn2a occurs in PanIN-2; and the loss of p53 and smad4 occurs in the later stage of precursor lesions. A series of other mutations cooperate to promote the tumorigenesis and metastasis of PDAC.

Fig. 3. Pathways of key driver genes and therapeutic targets in pancreatic cancer.

Oncogenic mutations in KRAS activate downstream signaling pathways, such as the PI3K/Akt/mTOR, KRAS/Ral, and KRAS/Raf/MEK pathways. Therapeutic methods include directly targeting KRAS, targeting upstream EGFR, or targeting downstream effectors such as PI3K, Akt, mTOR, Raf and MEK. Loss-of-function mutations in CDKN2A/TP53/SMAD4 attenuate the tumor suppressive functions of downstream signaling pathways. Therapeutic targets for tumor suppressor genes include restoring the function of wild-type p53, HSP90 inhibitors, vaccine therapy targeting mut-p53, Wee-1 kinase inhibitors (not shown), CDK4/6 inhibitors and TGF-β inhibitors.

Fig. 4. DNA damage repair pathway and the mechanism of PARP inhibitors.

DNA damage repair mainly includes the repair of DSBs and SSBs. PARP and ATR/CHK1 are responsible for SSB repair, while ATM, BRCA1/2 and other BRCAness-related genes are necessary for the homologous recombination repair of DSBs. PARP inhibitors block the repair of SSBs and increase DSBs. Mutations in germline BRCA1/2 or other BRCAness-related genes impair the homologous recombination repair of DSBs, leading to the accumulation of DSBs. The dysfunction of two pathways causes synthetic lethality, genomic instability and cell death.