KRAS Combination Therapy for EMT-Driven Resistance in PDAC

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Solution Overview

Problem

Existing KRAS-targeted therapies for cancers, particularly pancreatic ductal adenocarcinoma (PDAC), face transient tumor growth suppression due to epithelial-to-mesenchymal transition (EMT) and EMT-associated therapy resistance, driven by elevated TGFβ levels in the tumor microenvironment.

Innovation Solution

Administering a combination of KRAS inhibitors and TGFβ pathway inhibitors, such as SMAD, NFAT5, or S100A4 inhibitors, to target TGFβ signaling and prevent resistance, potentially combined with agents to block macrophage infiltration and re-polarize tumor-associated macrophages.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If KRAS inhibitors are used to treat KRAS mutant cancers, then tumor growth suppression is achieved, but therapy resistance develops due to EMT

Engineering Contradiction:

Improvetumor growth suppressionVSAvoidtherapy resistance

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent combines KRAS inhibitors with TGFβ pathway inhibitors (SMAD inhibitors, NFAT5 inhibitors, or S100A4 inhibitors) to create a composite therapy that simultaneously targets both KRAS signaling and EMT mechanisms, preventing resistance while maintaining tumor suppression efficacy

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent applies preliminary anti-action by pre-targeting the TGFβ pathway and EMT transcription factors before resistance can fully develop, using inhibitors that block TGFβ signaling upstream of EMT induction to prevent the resistance mechanism from establishing

Inventive Principle:

Principle #9Preliminary anti-action

2Adaptability or versatility

If TGFβ pathway is activated in the tumor microenvironment, then EMT is driven, but tumor suppression by KRAS inhibitors is reduced

Engineering Contradiction:

ImproveEMT driver activationVSAvoidtumor suppression

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent applies anti-weight by using TGFβ pathway inhibitors that counterbalance and oppose the pro-EMT effects of TGFβ activation, creating a net effect that restores tumor suppression while neutralizing the adaptive EMT response

Inventive Principle:

Principle #8Anti-weight (Counterweight)

Data Source

PatentUS20250339520A1Compositions and methods for use in KRAS-targeted therapies for the treatment of cancer

Publication Date: 2025.11.06 RUTGERS THE STATE UNIV

AI summary

Methods and compositions for the treatment of cancer are disclosed herein. More specifically, disclosed herein are methods and compositions for the treatment of KRASi resistant cancers using NFAT5 inhibitors.