CRISPR-Drug Combinatorial Screening Identifies Effective Combination Treatments for MTAP-Deleted Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• CDKN2A/MTAP co-deletion is common in lung, glioblastoma, and pancreatic cancers, which have poor prognoses.
• PRMT5 is a therapeutic target in MTAP-null tumors, with novel MTA-cooperative PRMT5 inhibitors showing early clinical promise.
• Effective cancer treatment often requires combination therapies to overcome resistance and improve outcomes.

Purpose of the Study:

• To identify other pathways that, when targeted, can enhance the efficacy of MTA-cooperative PRMT5 inhibitors.
• To investigate synergistic effects between PRMT5 inhibition and other pathway inhibitors in CDKN2A/MTAP-deleted cancers.

Main Methods:

• Utilized a CRISPR library screen to identify genetic dependencies in MTAP-deleted cancers treated with MTA-cooperative PRMT5 inhibitors.
• Employed chemical inhibitors targeting components of the MAPK pathway (KRAS, MEK, ERK, RAF) in combination with PRMT5 inhibitors.
• Evaluated combination efficacy in vitro and in vivo models of CDKN2A/MTAP-null, RAS-active tumors.

Main Results:

• Loss of several genes, including MAPK pathway members, sensitized MTAP-deleted cancers to PRMT5 inhibition.
• Combined inhibition of PRMT5 and MAPK pathway members (KRAS, RAF) demonstrated synergistic tumor cell killing.
• In vivo studies showed complete responses when MTA-cooperative PRMT5 inhibitors were combined with KRAS or RAF inhibitors.
• Observed non-cross-reactive resistance mechanisms between KRAS and PRMT5 inhibitors.

Conclusions:

• Therapeutic combinations of MTA-cooperative PRMT5 inhibitors with MAPK pathway inhibitors (KRAS, RAF) show significant potential for treating CDKN2A/MTAP-deleted cancers.
• These combinations may offer improved response rates and overcome resistance in difficult-to-treat solid tumors.
• Further clinical investigation of these combination strategies is warranted to benefit patients.