This report describes a multigenic model of pancreatic carcinoma (pancreatic ductal adenocarcinoma) using a combination of Drosophila genes related to a number of human genes implicated in this disease: human KRAS (using an activated form of Dmel\Ras85D), human TP53 (using RNAi-knockdown targeted to Dmel\p53), and human SMAD4 (using RNAi-knockdown targeted to Dmel\Med). Action of a fourth human gene, CDKN2A, was approximated by targeted expression of Dmel\CycE (both are involved in regulation of the mitotic cell cycle).
UAS constructs of human genes Hsap\KRAS, Hsap\TP53, and Hsap\SMAD4 have been introduced into flies, but have not been used in the context of this disease model.
'4-hit' flies were generated using various GAL4 drivers. Wing-specify drivers resulted in epithelial transformations in the wing consistent with uncontrolled growth. More general GAL4 drivers resulted in decreased survival. A genetic screen identified MEK and AURKB as potential therapeutic targets.
[updated Dec. 2023 by FlyBase; FBrf0222196]
[PANCREATIC CANCER](https://omim.org/entry/260350)
[KRAS PROTOONCOGENE, GTPase; KRAS](https://omim.org/entry/190070)
[ACTIVIN A RECEPTOR, TYPE IB; ACVR1B](https://omim.org/entry/601300)
[TUMOR PROTEIN p53; TP53](https://omim.org/entry/191170)
[SMAD FAMILY MEMBER 4; SMAD4](https://omim.org/entry/600993)
[SERINE/THREONINE PROTEIN KINASE 11; STK11](https://omim.org/entry/602216)
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas accounting for more than 90% of all pancreatic malignancies. PDAC is the fourth most frequent cause of cancer-related deaths worldwide with a 5-year overall survival of less than 8%. (Orth et al., 2019; pubmed:31395068)
Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. [from MIM:260350; 2023.12.12]
Somatic mutations in pancreatic cancer occur in the KRAS, CDKN2A, SMAD4, TP53, ARMET, STK11, ACVR1B, and RBBP8 genes. [from MIM:260350; 2023.12.12]
One to one: 1 human gene to 1 Drosophila gene; multiple related genes in both species.
Many to one: 3 human genes to 1 Drosophila gene; multiple related genes in both species.
Many to one: 3 human genes to 1 Drosophila gene.
No moderate- to high-scoring ortholog of CDKN2A has been identified in Drosophila.
High-scoring ortholog of human KRAS, HRAS, and NRAS (1 Drosophila to 3 human; multiple related genes in both species).
Moderate-scoring ortholog of human TP53, TP63, TP73 (1 Drosophila to 3 human).
High-scoring ortholog of human SMAD4 (1 Drosophila to 1 human; multiple related genes in both species).