Loss of LGR5 through Therapy-induced Downregulation or Gene Ablation Is Associated with Resistance and Enhanced...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Leucine-rich repeat-containing, G protein-coupled receptor 5 (LGR5) is a key marker in colorectal cancer (CRC) and cancer stem cells (CSCs).
• LGR5 expression is linked to tumor initiation, progression, metastasis, and therapy sensitivity.
• Mechanisms underlying LGR5 loss-induced therapy resistance in CRC are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which LGR5 loss contributes to therapy resistance in colorectal cancer.
• To investigate the role of STAT3 and MET signaling in LGR5-mediated drug resistance.
• To evaluate the therapeutic potential of targeting the MET-STAT3 pathway in combination with standard therapies.

Main Methods:

• Induction of LGR5-negative (LGR5-) state in LGR5-positive (LGR5+) colorectal cancer cells via chemotherapy, antibody-drug conjugates (ADCs), or gene ablation.
• Assessment of STAT3 and MET pathway activation using molecular assays.
• In vitro and in vivo experiments involving MET-STAT3 inhibitors, irinotecan, and ADCs in CRC cells, organoids, and xenografts.

Main Results:

• Loss of LGR5 in CRC cells leads to STAT3 activation mediated by increased MET receptor activity.
• LGR5 overexpression reduces MET-STAT3 activity, sensitizing cells to therapy.
• A feedback loop exists between STAT3 and LGR5/MET signaling.
• Combination therapy with MET-STAT3 inhibitors and irinotecan or ADCs demonstrated synergistic effects in vitro and in vivo.

Conclusions:

• Drug-resistant LGR5- CRC cells survive by activating the MET-STAT3 pathway.
• Targeting the MET-STAT3 axis offers a promising strategy to overcome therapy resistance in colorectal cancer.
• Combined inhibition of MET-STAT3 with chemotherapy or ADCs warrants further clinical investigation.