Epigenetic inhibition of adaptive bypass responses to lapatinib by targeting BET Bromodomains

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Kinases are key drivers in cancer, leading to over 30 FDA-approved targeted kinase inhibitors.
• Current kinase inhibitors often lack clinical durability due to adaptive cellular responses.
• These adaptive responses involve the kinome and transcriptome, bypassing targeted inhibition.

Purpose of the Study:

• To develop a novel method for achieving durable responses to kinase inhibition.
• To address the challenge of therapeutic resistance in cancer treatment.
• To investigate epigenetic mechanisms for overcoming adaptive resistance.

Main Methods:

• Characterization of oncogenic kinases and their role in cancer.
• Analysis of adaptive kinome and transcriptome responses to targeted therapies.
• Development and application of an epigenetic-level intervention strategy.

Main Results:

• Identification of specific adaptive mechanisms that confer resistance to kinase inhibitors.
• Demonstration of a novel epigenetic method to prevent these adaptive responses.
• Achieved durable therapeutic responses in preclinical models by targeting epigenetic pathways.

Conclusions:

• Epigenetic modulation offers a promising strategy to overcome adaptive resistance to kinase inhibitors.
• This approach has the potential to significantly improve the clinical durability of targeted cancer therapies.
• Preventing adaptive responses at an epigenetic level is crucial for long-term treatment efficacy.