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Published on: September 30, 2016
Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer
Abstract:
MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.
Insights
MAPK pathway inhibitors (MAPKi) offer limited durability in colorectal cancer. New research identifies adaptive plasticity tumor (APT) cells, driven by ASCL2, that resist MAPKi, suggesting targeting plasticity can improve treatment outcomes.
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.
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