by Li Yuan, Chinese Academy of Sciences
A research team led by Prof. Wang Yuexiang
from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese
Academy of Sciences discovered a novel oncogenic driver gene in human lung
cancer, the leading cause of cancer-related mortality worldwide.
Their findings were published in Journal of
Experimental Medicine on June 18.
Approximately 85% of all lung cancer cases
are non-small cell lung cancers (NSCLCs). Although tyrosine kinase inhibitors
and immunotherapy have contributed to survival benefits in some patients, the
overall survival rates for NSCLCs remain low.
Patients with NSCLC that are driven by KRAS
mutations are often unresponsive to tyrosine kinase inhibitors and have a poor
prognosis. Although inhibitors for the KRASG12C mutant have been approved to
treat NSCLC patients, a general strategy that targets all KRAS mutants remains
elusive.
Central precocious puberty (CPP) is largely
caused by germline mutations in the MKRN3 gene. Interestingly, CPP has been
epidemiologically linked to various diseases in adulthood, including cancers.
Cohorts of individuals with CPP show an increased risk of malignancies such as
lung cancers.
To investigate whether central precocious
puberty-associated MKRN3 gene is mutated in human cancers, the research team
led by Prof. Wang Yuexiang queried The Cancer Genome Atlas (TCGA) Pan-Cancer genomic
data sets. Strikingly, MKRN3 is frequently mutated in NSCLCs. MKRN3 aberrations
are significantly enriched in human NSCLC samples harboring oncogenic KRAS
mutations.
The researchers further presented genetic,
functional, mouse models and mechanistic data that identify the central
precocious puberty-associated gene MKRN3 gene as a bona fide tumor suppressor
in NSCLC. They uncovered its tumor suppressing mechanism and highlighted
MKRN3-PABPC1 axis deregulation as a key pathway in lung cancer oncogenesis.
MKRN3 inactivation led to lung cancer
proliferation and progression through PABPC1 ubiquitination mediated global
protein synthesis. MKRN3 restoration in MKRN3-inactivated NSCLC suppressed
tumor growth in nude mice. Therefore, molecular interventions targeting MKRN3
deficiency may have therapeutic potential for KRAS-mutant NSCLC treatment.
These findings showed that biological
mechanisms of central precocious puberty are relevant in tumorigenesis, which
may help in developing anticancer drugs.