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

Abstract

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Integrative Analysis of the Genomic and Immune Microenvironment Characteristics Associated With Clear Cell Renal Cell Carcinoma Progression: Implications for Prognosis and Immunotherapy

“…The relationship of CDKN2A and CDKN2B expression with the corresponding SCNA levels seemed to indicate that complex pathways regulated their transcription levels and that their tumor suppressor properties were not evident in ccRCC. MTAP is another tumor suppressor in Del(9p21.3) ( 63 – 65 ). Xu et al.…”

Somatic 9p24.1 alterations in HPV – head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity

“…More recently, SCNAs, notably losses containing IFNs and IFN pathway genes, many on chromosome 9p, have been reported to predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors ( 1 , 21 ). Immunogenetic studies of 9p21.3 copy number alterations, focused primarily on CDKN2A deletion ( 22 , 23 ), can encompass a cluster of 16 type-I IFN genes ( Fig. 1 A ) involved in antitumor immune responses ( 24 ), while IFN-γ pathway gene alterations at 9p24.1 have been reported to correlate with immune-cold, ICT-resistant tumors, primarily in metastatic melanoma ( 25 ).…”

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas

“… 15 9p21.3 loss has been reported to correlate with a cold tumor immune microenvironment and primary resistance to single-agent ICT. 19 Nonetheless, several strategies are actively being developed in combination with immune checkpoint blockade to modulate the tumor immune microenvironment in various solid cancers with 9p21.3 loss, such as antifolates, 20 PRMT inhibitors, 21 anti-adenosine, 20 and CDK4/6 inhibitors. 22 In this context, Sun et al recently showed that tRCC are cold tumors when compared with clear-cell RCC, with the exception of a subset harboring MED15-TFE3 fusions.…”