Modulating 19S Proteasome Subunits to Overcome Inhibitor Resistance
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Solution Overview
Problem
Current proteasome inhibitors, such as bortezomib, face limitations due to intrinsic and acquired resistance in cancer cells, reducing their effectiveness in treating hematopoietic tumors, as the molecular mechanisms underlying resistance are not fully understood.
Innovation Solution
Modulating the expression or activity of 19S proteasome subunits in cancer cells to either increase or decrease resistance to proteasome inhibitors, using agents like RNAi, antisense nucleic acids, or small molecules to target specific subunits, thereby identifying vulnerabilities and enhancing sensitivity to proteasome inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If proteasome inhibitors are used to treat cancer, then cancer cell death is induced, but resistance develops reducing treatment effectiveness
Solution Approach 1:
The patent applies preliminary action by modulating 19S subunit expression levels before proteasome inhibitor treatment to prevent resistance development. By pre-adjusting the proteasome regulatory complex composition, the cancer cells are rendered more susceptible to inhibitor effects, ensuring treatment effectiveness before resistance can emerge
Solution Approach 2:
The patent employs parameter changes by modifying the expression levels of 19S proteasome subunits as a controllable variable. By changing this specific parameter (19S subunit expression), the patent optimizes cancer cell sensitivity to proteasome inhibitors, thereby improving treatment reliability while preventing adaptive resistance
2Reliability
If 19S subunit expression is reduced to increase resistance, then cancer cell survival is enhanced, but sensitivity to proteasome inhibitors decreases
Solution Approach 1:
The patent applies inversion by reversing the conventional understanding of 19S subunit expression. Instead of reducing 19S subunits to increase survival (which decreases inhibitor sensitivity), the patent increases 19S subunit expression to enhance cancer cell survival while simultaneously maintaining or improving inhibitor sensitivity, thereby resolving the harmful trade-off
3Productivity
If proteasome inhibitor resistance is increased, then cancer cell proliferation is maintained, but treatment response is reduced
Solution Approach 1:
The patent uses 19S proteasome subunits as an intermediary element to mediate between cancer cell proliferation and treatment response. By modulating 19S subunit expression, the patent creates a state where cancer cells can maintain controlled proliferation while remaining responsive to proteasome inhibitors, thus resolving the contradiction between productivity and treatment reliability
Data Source
AI summary
In some aspects, the disclosure provides methods of modulating the level of proteasome inhibitor resistance of a cell, the methods comprising manipulating the level of expression or activity of a subunit of the 19S proteasome in the cell. In some aspects, cells in which the level of a 19S subunit is modulated, e.g., reduced, are provided. In some aspects, methods of identifying agents that reduce proteasome inhibitor resistance are provided. In some aspects, methods of classifying cancers according to predicted proteasome inhibitor resistance are provided. In some aspects, methods of killing or inhibiting proliferation of cancer cells, e.g., proteasome inhibitor resistant cancer cells, are provided. In some aspects, methods of treating cancer, e.g., proteasome inhibitor resistant cancer, are provided.