Placing purines in precision medicine: Targeting a metabolic reliance in KRAS-mutant tumors

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Precision oncology often relies on genomic mutations for targeted therapies.
• Monotherapy in cancer treatment can be insufficient and lead to drug resistance.
• Functional drug screening complements molecular testing to identify tumor-specific drug sensitivities.

Purpose of the Study:

• To introduce a multi-omic paradigm, REFLEX (resistance evaluation after first line exposure), for prioritizing drug combinations.
• To identify synergistic drug combinations for KRAS-mutant cancers using drug-induced molecular changes.

Main Methods:

• Utilized a resistance evaluation after first line exposure (REFLEX) multi-omic approach.
• Investigated drug-induced molecular changes in KRAS-mutant cancer models.
• Performed functional drug screening and combination screening.

Main Results:

• Trametinib treatment in KRAS-mutant models dysregulated the purine biosynthetic pathway by reducing GART enzyme levels.
• This induced vulnerability identified 6-thioguanine as a synergistic partner.
• Trametinib-induced GART loss predicted sensitivity to the combination therapy in KRAS-mutant cancer models.
• Combination therapy significantly increased overall survival in vivo without systemic toxicity.

Conclusions:

• Integrating drug-induced multi-omic changes with functional screening can identify effective therapeutic strategies.
• Purine analogs combined with MEK inhibitors show promise for treating KRAS-mutant tumors.
• The REFLEX paradigm aids in prioritizing effective combination therapies.