Pancreatic cancer is an atypical gastrointestinal malignant tumor with hidden clinical symptoms. Due to the difficulties in diagnosis, high mortality, and low cure rate, it is known as the "King Of Cancer". The KRAS mutation is found in about 93% of patients, and the most frequent one is KRAS G12D subtype mutation, accounting for about 40%, followed by G12V, G12R, G12C and others ^[1].

Although the KRAS G12D mutation is more common in Pancreatic Ductal adenocarcinoma (PDCA), there is currently no approved targeting drug for the KRAS G12D mutation in the world. Instead, three targeting drugs for the KRAS G12C mutation, Krazati(adagrasib), Lumakras(sotorasib) and Dalbert (Fluzereset), are approved for use in non-small cell lung cancer that has previously received at least one systemic therapy and carries the KRAS G12C mutation.

Compared to KRAS G12C, KRAS G12D is a different species of amino acid mutation at the same codon. KRAS G12D is a mutation at KRAS 12 codon that introduces aspartic acid instead of cysteine. KRAS G12C is mainly distributed in the field of lung cancer, while KRAS G12D is mainly distributed in the field of pancreatic cancer. This further results in the inability of the KRAS G12C inhibitor to be directly used in the treatment of KRAS G12D mutant tumors, since aspartic acid cannot form covalent bonds with the KRAS G12C inhibitor.

Currently, a variety of KRAS G12D inhibitors have been developed, and the information of some drugs is shown in the following table ^[2]. Most of these KRAS G12D inhibitors under development are in the early clinical research stage, and the earliest stage is stage 1/2.

The types of KRAS G12D inhibitors under investigation are different, and they involve small-molecule drugs, degradants and TCR-T cell drugs. Next, we will briefly understand the action mechanism or research progress of individual drugs.

01

FH375 is an oral KRAS G12D (on/off) inhibitor that inhibits the binding of downstream effector proteins by non-covalent binding of KRAS G12D protein, and destroys the continuous activation of downstream pathways by KRAS G12D in cells, finally efficiently inhibiting the proliferation of tumor cells. Preclinical studies have shown that GFH375 alone has a significant inhibitory effect on tumor growth.

02

MRTX-1133 was the first reported target of KRAS-G12D. MRTX1133 could inhibit the inactivation and activation of KRAS G12D mutant cells in two states, and it did not inhibit wild-type tumor cells, showing good inhibitory activity in both pancreatic and colon cancers.

03

HRS-4642 injection is the first clinically approved small-molecule innovative drug for advanced solid tumor with KRAS G12D mutation in China. The drug is prepared by liposome encapsulation, and is the first liposome KRAS G12D inhibitor in the world. It has excellent pharmaceutical characteristics such as targeted drug administration, passive targeting to tumor tissues by using different permeability and high permeability long retention effect, controllable and continuous drug release, and its Phase I clinical research was successfully selected for the preferred oral report at last year's ESMO Conference, and it is the first KRAS G12D inhibitor in the world that discloses clinical efficacy data.

04

NT-112 is the world's first clinically approved TCR-T cell drug targeting KRAS G12D. TCR-T therapy has unique advantages over CAR-T therapy in the treatment of solid tumors. Since MHC molecules can display peptide chains from cell surface and intracellular proteins, TCRs can recognize and attack more kinds of antigens and bind to tumor cells more widely, resulting in more uniform drug distribution.

05

ASP3082 is a PROTAC drug that induces ubiquitination of a target protein and is further degraded by proteasome. This process realizes the "catalytic degradation" of the target protein, which is different from the "one-on-one" structural inhibition mode of traditional small molecule inhibitors.

Summary

At present, the research progress of KRAS G12D inhibitor is relatively slow, but we are glad that it has been realized from "non-patent medicine". We are looking forward to an early major breakthrough in the field of KRAS G12D inhibitors. At present, many clinical trials are being recruited. For patients who have failed to receive standard treatment or have no standard treatment plan, they may benefit from clinical trials, ushering in new hopes.

References

[1] Semin Oncol. 2021 Feb; 48(1):10-18. 

[2] https://clinicaltrials.gov/

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