MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Methylthioadenosine phosphorylase (MTAP) deficiency is common in 9p21-deleted tumors.
• MTAP deficiency theoretically sensitizes tumors to antifolates targeting de novo purine synthesis.

Purpose of the Study:

• To assess the efficacy of pemetrexed in MTAP-deficient urothelial carcinoma (UC) via a phase II trial.
• To explore the synthetic lethal interaction between MTAP deficiency and de novo purine inhibition.

Main Methods:

• A single-arm phase II clinical trial (NCT02693717) evaluated pemetrexed in MTAP-deficient UC patients.
• Preclinical studies involved UC cell lines (in vitro) and xenografts (in vivo).
• Retrospective analysis of a lung adenocarcinoma cohort (N=72) from the BATTLE2 trial (NCT01248247) was performed.

Main Results:

• The phase II trial showed an overall response rate (ORR) of 43% (3/7 patients) to pemetrexed in MTAP-deficient UC.
• Historic and preclinical data indicated increased sensitivity to pemetrexed in MTAP-deficient models, with pemetrexed inducing DNA damage and nucleotide pool distortion.
• MTAP knockdown enhanced pemetrexed sensitivity in vitro and in vivo.
• In a lung adenocarcinoma cohort, MTAP deficiency correlated with improved response rates to pemetrexed.

Conclusions:

• MTAP deficiency confers sensitivity to pemetrexed, suggesting a synthetic lethal interaction with de novo purine synthesis inhibition.
• This interaction presents a promising therapeutic strategy for MTAP-deficient cancers, warranting larger prospective trials.