Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Molecularly targeted therapies like EGFR inhibitors have improved cancer treatment outcomes.
• Patients with KRAS and BRAF mutations in colorectal cancer often lack effective targeted therapy options.

Purpose of the Study:

• To investigate the potential of crenolanib, a novel molecularly targeted therapy, in treating colorectal cancer.
• To evaluate crenolanib's efficacy alone and in combination with cytotoxic agents in various colorectal cancer models.

Main Methods:

• Utilized multiple colorectal cancer cell lines and patient-derived organoids (PDOs) to assess crenolanib's growth-inhibitory effects.
• Examined crenolanib's impact on ERK and AKT/mTOR signaling pathways and stem cell marker expression (OCT4, NANOG, SOX2).
• Investigated crenolanib's effects in combination with cytotoxic drugs and its ability to abrogate growth factor-induced stem cell marker increases.

Main Results:

• Crenolanib suppressed ERK and AKT/mTOR pathways and inhibited growth in colorectal cancer cell lines with BRAF (HT29) and KRAS (HCT116) mutations.
• Additive or synergistic effects were observed when crenolanib was combined with other cytotoxic agents.
• Crenolanib demonstrated growth-suppressing effects in all tested PDOs, irrespective of KRAS/BRAF mutation status, and reduced stem cell marker expression.

Conclusions:

• Crenolanib exhibits significant anti-tumor activity in colorectal cancer models, including those with KRAS/BRAF mutations.
• The drug effectively targets key signaling pathways and reduces cancer stem cell markers.
• Crenolanib shows potential as a valuable therapeutic agent for colorectal cancer patients, particularly those with KRAS/BRAF mutations.