Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer

Area of Science:

• Oncology
• Cancer Biology
• Molecular Therapeutics

Background:

• MAPK pathway inhibitors (MAPKi) are crucial for advanced colorectal cancer (CRC) but often yield transient responses.
• Mechanisms beyond acquired mutations limiting MAPKi response durability in CRC remain largely unknown.

Purpose of the Study:

• To investigate novel tumor biology contributing to limited response durability in MAPKi-treated colorectal cancer.
• To explore the impact of tumor plasticity on therapeutic response to MAPKi.

Main Methods:

• Analysis of MAPKi-treated patient data and patient-derived CRC models.
• Assessment of stemness programs, ASCL2 expression, and adaptive plasticity tumor (APT) cell populations.
• Preclinical evaluation of APT cell depletion strategies in mice.

Main Results:

• MAPKi treatment correlates with activated stemness programs and increased ASCL2 expression, linked to poor outcomes.
• ASCL2 identifies a distinct, MAPKi-resistant cell population (APT cells) arising from tumor plasticity.
• MAPK pathway suppression promotes APT cell enrichment, limiting therapeutic efficacy in preclinical and clinical settings.

Conclusions:

• Adaptive plasticity tumor (APT) cells, characterized by ASCL2 expression, represent a key mechanism of MAPKi resistance in colorectal cancer.
• Targeting tumor plasticity and depleting APT cells can enhance MAPKi efficacy and prolong response durability.
• Addressing tumor plasticity is essential for improving clinical outcomes in colorectal cancer patients treated with MAPKi.