ERK and PI3K Inhibitor Combination for Resistant KRAS/PIK3CA Cancers
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Solution Overview
Problem
Existing cancer treatments targeting the MAPK and PI3K/Akt pathways face challenges due to genetic heterogeneity and acquired drug resistance, particularly in cancers with mutations affecting the PI3K pathway, necessitating novel therapies that can effectively target both pathways simultaneously.
Innovation Solution
Administering a combination of BVD-523, an ERK inhibitor, and BYL719, a PI3K/Akt pathway inhibitor, to treat or ameliorate the effects of cancer, particularly in subjects with somatic KRAS and PIK3CA mutations or those refractory to RAF or MEK inhibitor therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If MAPK pathway inhibitors are used alone, then initial response is achieved, but acquired drug resistance develops rapidly
Solution Approach 1:
The patent combines MAPK pathway inhibitors with PI3K/Akt pathway inhibitors into a single treatment regimen. This dual-pathway inhibition strategy addresses the technical contradiction by simultaneously targeting both MAPK and PI3K/Akt signaling pathways, thereby maintaining treatment efficacy over extended periods and delaying the onset of acquired drug resistance while preserving initial response rates.
Solution Approach 2:
The patent changes the treatment parameter from single-pathway inhibition to dual-pathway inhibition. By introducing PI3K/Akt pathway inhibition alongside MAPK pathway inhibition, the treatment parameters are expanded to cover multiple signaling pathways, thereby extending the duration of effective treatment and reducing the rate of acquired resistance.
2Reliability
If PI3K pathway mutations are present, then treatment efficacy decreases, but combination therapy can restore effectiveness
Solution Approach 1:
The patent employs a combination therapy regimen that simultaneously inhibits both MAPK and PI3K/Akt pathways, creating a universal treatment approach that addresses multiple genetic alterations. This multi-functional therapy can effectively treat cancers with various mutations including KRAS, NRAS, BRAF, and PIK3CA mutations, as well as wild-type tumors, thereby restoring treatment efficacy in the presence of PI3K pathway mutations while accommodating genetic heterogeneity.
3Ease of operation
If single-agent therapy is used, then treatment simplicity is maintained, but synergistic effects are lost
Solution Approach 1:
The patent merges MAPK pathway inhibition and PI3K/Akt pathway inhibition into a combined therapy regimen. This combination produces synergistic therapeutic effects that are greater than the sum of individual agent effects, thereby enhancing the power of the treatment while maintaining relative simplicity through coordinated administration of two targeted therapies.
Data Source
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AI summary
The present invention provides, inter alia, methods, kits, and compositions for treating or ameliorating the effects of a cancer in a subject in need thereof. This method includes administering to the subject an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is an inhibitor of the PI3K/Akt pathway or a pharmaceutically acceptable salt thereof. Also provided are methods of treating or ameliorating the effects of a subject with cancer in which the subject has a somatic KRAS and a somatic PIK3CA mutation or in which the cancer is refractory to a therapy selected from RAF inhibitor therapy, MEK inhibitor therapy, and RAF and MEK inhibitor therapy.