TITLE:
Exploration of Kras Mutations and Their Potential for Being a Target Molecule in Cancer Chemotherapy
AUTHORS:
Anusha Chinthareddy, Terry Oroszi
KEYWORDS:
KRAS Mutations, Non-Small Cell Lung Carcinoma (NSCLC), Colorectal Can-cer, MAPK Pathway, Chemotherapy
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.14 No.6,
June
16,
2023
ABSTRACT: The Rat sarcoma virus (RAS) family of proteins, which includes the
Kristen Rat sarcoma virus (KRAS), is linked to nearly one-fourth of all human
cancers. KRAS mutations, in particular, are associated with Non-Small Cell Lung
Carcinoma (NSCLC), colorectal cancer, adenocarcinomas, ovarian carcinoma, and endometrial
tumors. KRAS activates 80 different signaling pathways, including
Mitogen-activated protein kinases (MAPK) and Phosphoinositide 3-kinase (PI3K),
and up-regulates transcription factors such as ETS like Protein (ELK), Jun
Proto-Oncogene (JUN), and Myelocytomatosis (MYC), which are involved in cell
differentiation, proliferation, transformation, and survival. KRAS mutations
are also known to cause autocrine function, which further exacerbates the
situation. In NSCLC, KRAS mutations have a strong positive correlation with the
disease, particularly in patients with a smoking history. In pancreatic cancer,
KRAS mutations are a dominant pathological basis, with most mutations being
G12D, G12V, G13D, G13C, G13S, and G13R. These mutations serve as initial markers
in tumorigenesis and are associated with poor prognosis and high mortality
rates. In colorectal cancer, KRAS mutations contribute to 4/5 of cases, with
cellular mechanisms involving the MAPK pathway, which resists anti-epidermal
growth factor antibodies. In Low-grade Serous Ovarian Cancer (LGSOC), KRAS
mutations are associated with altered signaling in the MAPK pathway and drug
resistance. However, treatments such as Selumetinib, a down regulator of
RAS/Rapidly Accelerated Fibrosarcoma (RAF)/Mitogen-activated protein kinase
(MEK) pathways, and a combination of trametinib and buparlisib have shown
promise in managing LGSOC when diagnosed early through KRAS mutation markers.
Although KRAS mutations are commonly associated with many types of cancer, their
use in clinical practice is limited due to the lack of accurate methods to
identify them. It is needed to further isolate the KRAS mutation products and
correlate the cancer-causing genes to make it a promising approach for cancer
chemotherapy.