XPO1 R749Q Mutations Co-occur with POLE Mutations in Cancer and Can Be Targeted to Overcome Chemoresistance

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Exportin-1 (XPO1) is crucial for cell survival and its mutations are found in cancer.
• Genomic analyses reveal recurrent XPO1 hotspot mutations in various cancers.

Purpose of the Study:

• To identify and characterize XPO1 variants in a large cohort of cancer patients.
• To investigate the functional and clinical implications of the XPO1 R749Q mutation.

Main Methods:

• Large-scale genomic analysis of 217,570 cancer patients.
• Isogenic cell line analysis and structural modeling of XPO1.
• Compound library screening and drug combination studies.
• Evaluation in xenograft mouse models.

Main Results:

• The XPO1 R749Q mutation was identified across solid tumors, enriched in endometrial and colorectal cancers, and co-occurred with POLE mutations.
• XPO1 R749Q enhanced protein export and conferred resistance to topoisomerase I inhibitors.
• Combination therapy with XPO1 and topoisomerase I inhibitors demonstrated synergistic antitumor effects and overcame resistance in preclinical models.

Conclusions:

• XPO1 alterations, particularly R749Q, are selected in POLE-mutant tumors and associated with chemoresistance.
• Targeting XPO1 in combination with topoisomerase I inhibitors offers a promising therapeutic strategy for patients with XPO1 R749Q-mutant cancers.