KRAS G12C Combination Therapy for Selective Tumor Killing
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Solution Overview
Problem
Current treatments for cancers with KRAS mutations, such as pancreatic, lung adenocarcinoma, and colorectal cancer, lack effective therapies that target KRAS mutant tumors without causing on-target toxicities in normal cells, and existing MAPK pathway inhibitors are ineffective or contra-indicated.
Innovation Solution
A combination therapy using a KRASG12C inhibitor, such as AMG 510, in combination with additional therapeutic agents like anti-PD-1 antibodies, chemotherapeutics, MEK inhibitors, EGFR inhibitors, TOR inhibitors, SHP2 inhibitors, PI3K inhibitors, or AKT inhibitors, to treat cancers with KRAS mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If MAPK pathway inhibitors are used to treat KRAS mutant tumors, then tumor growth may be inhibited, but on-target toxicities occur in normal cells and the therapy is often ineffective or contra-indicated
Solution Approach 1:
The patent applies local quality by making the KRASG12C inhibitor selective for mutant KRAS cells through covalent binding to the cysteine residue at position 12, which is only present in the mutant form. This allows the drug to target tumor cells with KRASG12C mutations while sparing normal cells that lack this specific mutation, thereby achieving therapeutic efficacy without on-target toxicities in normal tissue
Solution Approach 2:
The patent uses covalent bonding as an intermediary mechanism where the inhibitor forms a stable covalent bond with the cysteine residue in the KRASG12C mutant protein. This covalent interaction serves as a mediator that ensures selective and irreversible inhibition of the mutant protein, preventing off-target effects on wild-type KRAS and other normal proteins
2Reliability
If combination therapy with multiple agents is used to enhance tumor-cell killing, then therapeutic efficacy is improved, but treatment complexity increases
Solution Approach 1:
The patent merges multiple therapeutic mechanisms into a unified treatment approach by combining KRASG12C inhibition with immune checkpoint inhibition and other targeted therapies. This combination strategy integrates different mechanisms of action (direct tumor cell killing, immune system activation, and pathway inhibition) into a coordinated treatment regimen that enhances overall efficacy while managing complexity through rational drug selection
3Reliability
If KRASG12C inhibitors are used to target mutant tumors, then selective anti-tumor activity is achieved, but resistance mechanisms may develop
Solution Approach 1:
The patent applies preliminary action by using KRASG12C inhibition to create a pro-inflammatory tumor microenvironment and induce immunogenic cell death before implementing immune checkpoint inhibition. This preliminary targeting of the mutant KRAS pathway primes the tumor for subsequent immune-mediated destruction, establishing a sequence of actions that prevents resistance by attacking the tumor through multiple sequential mechanisms rather than relying on a single pathway
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enhances tumor-cell killing and immune cell infiltration, making the tumor microenvironment sensitive to immunotherapy, providing a transformative therapy for patients with KRAS mutant tumors.
Implementation Method 1
KRASG12C can be targeted with covalent small molecule inhibitors which react with the mutant cysteine adjacent to the switch II pocket (SIIP), locking KRAS in its inactive GDP-bound state
Data Source
AI summary
The present invention provides combination therapy that includes an KRASG12C inhibitor, such asor a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain an KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.