PKMYT1 kinase ameliorates cisplatin sensitivity in osteosarcoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cisplatin (DDP) is a primary treatment for osteosarcoma (OS), but drug resistance significantly reduces its effectiveness.
• Identifying mechanisms of DDP resistance is crucial for improving patient outcomes in osteosarcoma.

Purpose of the Study:

• To identify key regulators of DDP sensitivity in osteosarcoma cells.
• To elucidate the molecular mechanisms underlying DDP resistance mediated by identified regulators.
• To evaluate potential therapeutic strategies targeting these regulators.

Main Methods:

• A kinome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen was employed to identify DDP sensitivity regulators.
• Transcriptome sequencing was used to analyze gene expression changes.
• In vitro functional assays and analysis of patient-derived clinical specimens were performed.
• The effects of PKMYT1 inhibition on DDP sensitivity and DNA damage response pathways were investigated.

Main Results:

• Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) was identified as a critical regulator of DDP sensitivity in OS.
• PKMYT1 activation was observed in OS cells upon DDP treatment, contributing to chemoresistance.
• PKMYT1 silencing enhanced OS cell sensitivity to DDP.
• PKMYT1 promotes chemoresistance by phosphorylating nucleophosmin 1 (NPM1), impairing its SUMOylation and subsequently hindering DNA damage response factor recruitment (BRCA1, RAP80, RAD51) and double-strand break (DSB) repair.
• The PKMYT1 inhibitor RP6306 synergized with DDP, increasing its cytotoxicity.

Conclusions:

• PKMYT1 plays a significant role in mediating DDP resistance in osteosarcoma.
• Targeting PKMYT1 represents a promising therapeutic strategy to overcome DDP resistance in OS.
• Combination therapy with DDP and PKMYT1 inhibitors warrants further clinical investigation for osteosarcoma treatment.