Genetic Signature of Human Pancreatic Cancer and Personalized Targeting

Abstract

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.

Keywords: KRAS; PDAC (pancreatic ductal adenocarcinoma); driver mutations; personalized treatment.

Figure 7

Minimally phosphorylated Rb protein is an inhibitor of the cell cycle in the G1 phase. When it is phosphorylated by the cyclinD-CDK4/6 association, it releases E2F protein and allows cell cycle continuation. Inactivation of p16, whether by mutation or epigenetic inhibition, releases CDK4/6 inhibition, which phosphorylates Rb [186]. Green arrows refer to cell cycle. Blue arrow represents the incorporation of a non-mitotic cell to the cycle.

Figure 1

This is the most frequent evolution scheme of PDAC, which takes approximately 15 years to become symptomatic since the first pro-tumoral mutation occurs. In this figure, KRAS point mutation is the initiator of the tumor [13]. For this progression to take place, specific genes need to be mutated or epigenetically silenced. Since 1988, the association of KRAS mutation with pancreatic cancer has been well established [14]. However, there is another 10 or 15% of the cases (KRAS wild type tumors) in which a different driver gene must be playing a role.

Figure 2

KRAS activation and inactivation. GEFs: Guanine nucleotide Exchange Factors. GAPs: GTPase-activating proteins. KRAS is activated by GTP binding [127].

Figure 3

The main oncogenic pathways of KRAS activation are shown in the diagram: the MAPKinases [128,129] are on the left and the PI3K/AKT/mTOR [130] are on the right. While the MAPKinases mediate proliferative signals, the PI3K pathway enhances survival, resistance to apoptosis and synthesis of essential molecules necessary for growth and proliferation. Oncogenic mutations in KRAS stabilizes its binding with GTP, leading to the constitutive activation of its downstream signaling.

Figure 4

The experiment by Morton et al. [162] showed that TP53 gene and p53 protein acted as a “stop” against the expression of the malignant phenotype of KRAS transformed cells. Once TP53 is mutated with loss of function, the mutated oncogenic KRAS is fully able to develop the malignant phenotype. This is clear evidence of TP53’s tumor-suppressing abilities.

Figure 5

TP53 gene/protein exerts a homeostatic effect on the cell, protecting the genome, and if this cannot be preserved, eliminating the cell through apoptosis or inducing senescence. p53 protein is attached to another protein known as MDM2 (murine double minute 2), which impedes p53 activation and drives it to proteasomal destruction. p53 activation requires that it be released from MDM2 [167]. It goes beyond the scope of this paper to discuss the details and intricacies of the p53 transcription factor. For a review, see Tanaka et al. [168].

Figure 6

BRCA1 or BRCA2 mutations lead to difficulties in DNA repair. Inhibition of PARP enzymes further increases these difficulties. PARP enzymes are essential for single-strand break repair. Their inhibition produces a collapse of the mitotic fork, indirectly generating double-strand breaks that cannot be repaired when BRCA mutations are present, therefore inducing apoptosis [175]. This is known as synthetic lethality. In addition to Olaparib, there are other approved PARP inhibitors such as rucaparib and niraparib, which have a similar mechanism of action.

Figure 8

(Left panel) The SMAD pathway. Upper right panel: Pro-tumoral effects of TGF-β. (Lower right panel) Anti-tumoral effects of the SMAD-TGF-β pathway. Purple arrow represents transcription. Light blue arrows mean effects.

Figure 9

The series of mutations that drive locally invasive PDAC. See text for details.

Figure 10

Distant metastasis can occur earlier when there is a SMAD4 mutation. See text for details.