A research article describing a novel therapeutic target in human pancreatic cancer, entitled “Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma” was published online in the scientific journal EMBO Mol Med on April 3rd, 2024.
Pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of pancreatic cancer, is one of the deadliest human malignancies with an overall 5-year survival rate of < 12% due to the lack of effective treatments. These statistics have not changed despite decades of research and therapeutic development. PDAC is predicted to become the second leading cause of cancer mortality by the year 2030. The current actively investigated targets are KRASG12C and mutant-BRCA. Unfortunately, only a small subgroup of PDAC patients harbor the KRASG12C (approximately 1%) or BRCA mutant (less than 9%).
To systemically identify the genetic vulnerabilities of PDAC, a research team led by Prof. WANG Yuexiang from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (SINH) performed genome-wide CRISPR screens on human PDAC models.
PKMYT1 was identified as a genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo. Pharmacological inhibition of PKMYT1 effectively induces tumor regression without overt toxicity in PDAC cell line–derived xenograft and in more clinically relevant patient-derived xenograft models.
Mechanistically, in addition to its canonical functions as a negative regulator of CDK1, proteomic screens demonstrate that PKMYT1 interacts with PLK1 in PDAC. PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, they show that TP53 mutation status and PRKDC activation modulate the sensitivity of PDAC to PKMYT1 inhibition.
PDAC remains challenging to treat, and targeted therapy at all levels remains a priority. PKMYT1 inhibition regulates multiple downstream pathways to maximize treatment effects for PDAC. Availability of PKMYT1 inhibitors makes it possible to translate the discovery into a clinical scenario. Hence, these intriguing findings open the door to the development of targeted therapies for PKMYT1-aberrant PDAC patients.
The research was supported by Profs. WANG Liwei and CUI Jiujie from Ren Ji Hospital, Prof. YANG Sheng from Fujian Medical University Union Hospital, and Prof. LU Yuan from Fudan University. This study was financially supported by Ministry of Science and Technology of China, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality.
A model depicting how the PKMYT1 pathways control cell proliferation and progression in pancreatic cancer. Left: The pancreatic cancer cells with high PKMYT1 expression. Right: The pancreatic cancer cells withPKMYT1 inhibition.
(Image by Prof. WANG Yuexiang’s group)
Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn
Web: http://english.sinh.cas.cn/
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