Genome-Wide Screening in Haploid Stem Cells Reveals Synthetic Lethality Targeting MLH1 and TP53 Deficient Tumours

Area of Science:

• Cancer Biology
• Genetics
• Pharmacology

Background:

• Synthetic lethality is a promising strategy for targeted cancer therapy.
• MLH1 and TP53 are critical cancer-related genes frequently altered in tumors.
• Identifying synthetic lethal interactions can reveal novel therapeutic targets.

Purpose of the Study:

• To discover genes that induce synthetic lethality when mutated alongside MLH1 or TP53.
• To validate these synthetic lethal interactions using small molecule inhibitors.
• To assess the therapeutic potential of identified targets in preclinical cancer models.

Main Methods:

• Genome-wide genetic screening in haploid human embryonic stem cells (hESCs).
• Introduction of loss-of-function mutations in MLH1 or TP53.
• Validation of synthetic lethal interactions using genetic and chemical approaches.
• Preclinical testing of small molecule inhibitors in cancer cell lines and xenograft models.

Main Results:

• Identified EXO1, NR5A2, and PLK2 as synthetic lethal partners for MLH1.
• Identified MYH10 as a synthetic lethal partner for TP53.
• Demonstrated selective killing of MLH1-null tumors with BI2536 (PLK2 inhibitor).
• Showcased selective killing of TP53-mutated tumors with blebbistatin (MYH10 inhibitor).

Conclusions:

• This study reveals novel synthetic lethal interactions for MLH1 and TP53.
• The identified targets and small molecules show potential for personalized cancer medicine.
• Genome-wide screening in haploid hESCs is a robust approach for cancer therapeutic discovery.