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▎WuXi AppTec content team editor
KRAS G12D is the most common mutation in the KRAS gene, occurring in
about 34% of pancreatic cancers, 10-12% of colorectal cancers, 4% of lung adenocarcinomas, 11% of biliary tract cancers, and other cancer types.
However, since the KRAS G12D mutant does not carry the cysteine found in the KRAS G12C mutant, it cannot be targeted with a covalent inhibition strategy targeting KRAS G12C
.
The researchers tested the anticancer activity
of MRTX1133 in a series of tumor models of human cell line transplantation or patient tissue transplantation that carry the KRAS G12D gene mutation.
The experimental results showed that in 25 KRAS G12D mutant tumor models, MRTX1133 caused tumor shrinkage by more than 30%
in 11 models.
KRAS gene mutation is one of the first oncogene mutations to be discovered, and it was once a well-known "undruggable" target
.
Last year, the US FDA accelerated the approval of the KRAS G12C inhibitor Lumakras developed by Amgen, declaring that the "undruggable" nature of KRAS was broken
.
After the KRAS G12C mutant was successfully targeted, the researchers turned their attention to other KRAS mutants that are common in a variety of
cancers.
Recently, the research team of Mirati Therapeutics published the results
of its preclinical trial of the KRAS G12D targeted therapy MRTX1133 in Nature Medicine.
The experimental results showed that MRTX1133 can bind to KRAS G12D with high affinity and specificity, and show anticancer activity
in a variety of tumor models carrying KRAS G12D.
In particular, in pancreatic cancer tumor models, MRTX1133 observed a response
in 8/11 (73%) of pancreatic cancer models.
KRAS G12D is the most common mutation in the KRAS gene, occurring in
about 34% of pancreatic cancers, 10-12% of colorectal cancers, 4% of lung adenocarcinomas, 11% of biliary tract cancers, and other cancer types.
However, since the KRAS G12D mutant does not carry the cysteine found in the KRAS G12C mutant, it cannot be targeted with a covalent inhibition strategy targeting KRAS G12C
.
Through a structure-based drug design strategy, the Mirati team discovered MRTX1133, a non-covalent inhibitor that binds to the inactivation and activation of KRAS G12D and inhibits the activity
of KRAS G12D.
It is highly selective for KRAS G12D, which is more than 1000 times more
selective than wild-type KRAS.
The researchers tested the anticancer activity
of MRTX1133 in a series of tumor models of human cell line transplantation or patient tissue transplantation that carry the KRAS G12D gene mutation.
The experimental results showed that in 25 KRAS G12D mutant tumor models, MRTX1133 caused tumor shrinkage by more than 30%
in 11 models.
MRTX1133 showed particularly significant anticancer activity in pancreatic cancer models, with 8 models (73%) of the 11 models showing tumor shrinkage of more than 30%.
The researchers also used CRISPR screening to analyze the feedback signaling pathway and bypass pathway excited by MRTX1133, and found that the activation of EGFR and PI3Kα signaling pathways may be the reason why
tumors develop drug resistance to MRTX1133.
The combination of MRTX1133 with the EGFR inhibitor cetuximab showed stronger anticancer activity
in a pancreatic cancer model.
The researchers point out that the study showed that KRAS G12D is a mutation
in an oncogenic driver gene in pancreatic cancer.
The results also demonstrate the feasibility of using small molecule drugs to specifically target KRAS G12D mutants, and discover the potential therapeutic strategy
of MRTX1133 in combination with other targeted therapies.
It is expected that this innovative therapy will enter the clinical development stage as soon as possible and demonstrate its anti-cancer efficacy
in human trials.
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