Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cellular Signaling

Background:

• Drug-induced cellular adaptation is a key mechanism of resistance to anti-cancer kinase inhibitor therapies.
• Understanding the dynamic cellular events following kinase inhibition is crucial for developing effective treatment strategies.

Purpose of the Study:

• To resolve the scale and kinetics of subcellular events after oncogenic BRAF inhibition in melanoma cells.
• To identify adaptive signaling networks that promote drug tolerance and cell cycle re-entry.

Main Methods:

• Utilized mass spectrometry-based phosphoproteomics and RNA sequencing (RNA-seq) to dynamically monitor thousands of growth- and survival-related signals.
• Analyzed data over minutes, hours, and days following oncogenic BRAF inhibition in human melanoma cells.

Main Results:

• Observed sustained inhibition of the BRAF-ERK pathway and gradual downregulation of cell cycle signaling.
• Identified three distinct, reversible phase transitions toward cellular quiescence.
• Revealed compensatory induction of SRC family kinase (SFK) signaling, partly mediated by reactive oxygen species.

Conclusions:

• Early adaptive signaling, particularly SFK induction, is a critical determinant of drug tolerance.
• Co-treatment with an SFK inhibitor demonstrated enhanced efficacy in vitro and in vivo.
• Assessing early drug-induced adaptive signaling holds translational potential for optimizing cancer therapy.