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Sword refers to the "king of cancer", a variety of KRAS inhibitors show anti-cancer activity

 Last Update: 2021-10-22
 Source: Internet
 Author: User

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Pancreatic cancer is one of the cancer types with the highest fatality rate among all solid tumors, which has also earned it the title of "King of Cancer"

An important feature of pancreatic cancer is that about 95% of tumors carry KRAS gene mutations, and it is also one of the tumor types most dependent on KRAS gene mutations

An important feature of pancreatic cancer is that about 95% of tumors carry KRAS gene mutations.

Picture source: reference [5]

KRAS G12C inhibitor reaches 50% remission rate

Mirati Therapeutics' adagrasib is a specific KRAS G12C inhibitor , which has shown promising anti-cancer activity in the treatment of patients with non-small cell lung cancer and colorectal cancer

adagrasib is a specific KRAS G12C inhibitor.

▲Preliminary clinical trial results of Adagrasib in the treatment of pancreatic cancer patients with KRAS G12C mutation (screenshot source: AACR)

KRAS G12D inhibitor exhibits anti-cancer activity

However, the KRAS G12C mutation is a rare type of KRAS mutation in pancreatic cancer .

In pancreatic cancer, the proportion of other mutation types such as KRAS G12D and KRAS G12V is higher

▲KRAS gene mutations in pancreatic cancer drive cancer (picture source: reference [4])

Mirati also announced the results of preclinical trials of its KRAS G12D inhibitor MRTX1133

MRTX1133 is a non-covalent KRAS G12D specific inhibitor that can bind to KRAS G12D mutants in inactive and activated states, and shows specificity for KRAS G12D mutants

▲MRTX1133 is a specific KRAS G12D inhibitor (screenshot source: AACR)

In preclinical animal studies for multiple cancer types, MRTX1133 significantly reduced tumor size, especially in pancreatic cancer tumor models.

MRTX1133 was observed to respond in 8/11 (73%) pancreatic cancer models

▲MRTX1133 reduces tumor size in a variety of cancer models

Pan-KRAS inhibitors inhibit the growth of multiple KRAS mutant tumors

Revolution Medicines presented the results of preclinical trials of the pan-KRAS inhibitor RMC-6236

When the activated KRAS protein binds to the chaperone protein cyclophilin A protein, it can form a pocket that can be targeted by small molecule drugs

▲ RMC-6236 can be combined with the activation state of a variety of KRAS mutants (picture source: Revolution Medicines official website)

In non-small cell lung cancer and pancreatic cancer animal models of tumor transplantation with different types of KRAS gene mutations, RMC-6236 showed good anti-cancer activity

▲RMC-6236 reduces tumor volume in non-small cell lung cancer and pancreatic cancer tumor models (picture source: Revolution Medicines official website)

In addition, RMC-6236 also showed the potential to change the tumor microenvironment and promote the anti-cancer immune response in in vivo experiments

Change the tumor microenvironment and promote the anti-cancer immune response.

Reference materials:

[1] AACR-NCI-EORTC VIRTUAL INTERNATIONAL CONFERENCE ON MOLECULAR TARGETS AND CANCER THERAPEUTICS.
Retrieved October 10.
2021.
from https:// -targets-and-cancer-therapeutics/abstracts/

[2] Discovery and Development of RAS(ON) Inhibitors Beyond KRASG12C.
Retrieved October 10.
2021.
from https://ir.
revmed.
com/static-files/ad588f56-5608-4ad6-9816-be40b38eb974

[3] Mirati Therapeutics to Present New Research From its Innovative Oncology Pipeline at the 2021 AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer.
Retrieved October 10.
2021.
from https://ir.
mirati.
com/press- releases/press-release-details/2021/Mirati-Therapeutics-to-Present-New-Research-From-its-Innovative-Oncology-Pipeline-at-the-2021-AACR-NCI-EORTC-Virtual-International-Conference- on-Molecular-Targets-and-Cancer/default.
aspx

[4] Waters et al.
, (2018).
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer.
Cold Spring Harb Perspect Med.
, doi: 10.
1101/cshperspect.
a031435

[5] Liu et al.
, (2019).
Targeting the untargetable KRAS in cancer therapy.
Acta Pharmaceutica Sinica B, https://doi.
org/10.
1016/j.
apsb.
2019.
03.
002

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