CRAF and ERK Inhibitor Combination for KRAS-Mutant Tumor Regression
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Solution Overview
Problem
Current therapies are ineffective for KRAS-mutant cancers, such as NSCLC, melanoma, pancreatic cancer, and ovarian cancer, as they lack targeted and well-tolerated treatments that result in durable responses.
Innovation Solution
A pharmaceutical combination of a CRAF inhibitor, Compound A, and an ERK inhibitor, Compound B, is administered simultaneously, separately, or sequentially to target the MAPK pathway, specifically inhibiting CRAF and ERK kinases to suppress tumor growth in KRAS-mutant tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for KRAS-mutant cancers, then treatment is provided, but the therapies are ineffective and lack durable responses
Solution Approach 1:
The patent segments the MAPK signaling pathway into multiple targetable components (CRAF, ERK, BRAF, MEK) and develops inhibitors for each segment. By dividing the therapeutic approach into multiple targeted interventions rather than a single therapy, the patent achieves more effective tumor control in KRAS-mutant cancers where previous monotherapies failed.
Solution Approach 2:
The patent combines multiple inhibitors (CRAF inhibitor, ERK inhibitor, BRAF inhibitor, MEK inhibitor) into combination therapies. This merging of multiple therapeutic agents targets different nodes in the MAPK pathway simultaneously, overcoming the ineffectiveness of single-agent therapies and achieving durable tumor regression in KRAS-mutant cancers.
2Adaptability or versatility
If targeted therapies are developed for KRAS-mutant cancers, then treatment specificity is improved, but resistance to BRAF and MEK inhibitors develops
Solution Approach 1:
The patent applies preliminary anti-action by combining CRAF and ERK inhibitors with BRAF and MEK inhibitors before resistance can develop. This preemptive combination therapy blocks alternative signaling routes that tumors might otherwise use to escape inhibition, preventing the emergence of resistant clones and maintaining durable responses in KRAS-mutant cancers.
Solution Approach 2:
The patent converts the harmful phenomenon of pathway compensation and resistance into a benefit by identifying and targeting the compensatory mechanisms themselves. By inhibiting CRAF and ERK alongside BRAF and MEK, the patent transforms the tumor's adaptive resistance mechanisms into additional therapeutic targets, achieving sustained efficacy where single agents failed.
3Duration of action of stationary object
If combination therapy is used to prevent resistance, then durability of response is improved, but treatment complexity increases
Solution Approach 1:
The patent develops multi-functional inhibitors that can target multiple nodes in the MAPK pathway (CRAF, ERK, BRAF, MEK) with single agents. This universality allows combination therapies to be achieved with fewer distinct compounds, reducing the logistical and administrative complexity of managing multiple specialized agents while maintaining the durability benefits of combination therapy.
Data Source
AI summary
The present invention relates to a combination treatment which comprises (a) at least one ERK inhibitor preferably Compound B as described herein, and (b) a c-RAF inhibitor or a pharmaceutically acceptable salt thereof, preferably Compound A, which may be combined into a single pharmaceutical composition or prepared for separate or sequential administration. It includes a c-RAF inhibitor and an ERK inhibitor prepared for simultaneous, separate or sequential administration for the treatment of a proliferative disease, particularly an advanced solid tumor that harbors a Mitogen-activated protein kinase (MAPK) alteration, and includes methods of using these compounds in combination as well as a commercial package comprising such combination.