TY - JOUR
T1 - MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
AU - Alhalabi, Omar
AU - Chen, Jianfeng
AU - Zhang, Yuxue
AU - Lu, Yang
AU - Wang, Qi
AU - Ramachandran, Sumankalai
AU - Tidwell, Rebecca Slack
AU - Han, Guangchun
AU - Yan, Xinmiao
AU - Meng, Jieru
AU - Wang, Ruiping
AU - Hoang, Anh G.
AU - Wang, Wei Lien
AU - Song, Jian
AU - Lopez, Lidia
AU - Andreev-Drakhlin, Alex
AU - Siefker-Radtke, Arlene
AU - Zhang, Xinqiao
AU - Benedict, William F.
AU - Shah, Amishi Y.
AU - Wang, Jennifer
AU - Msaouel, Pavlos
AU - Zhang, Miao
AU - Guo, Charles C.
AU - Czerniak, Bogdan
AU - Behrens, Carmen
AU - Soto, Luisa
AU - Papadimitrakopoulou, Vassiliki
AU - Lewis, Jeff
AU - Rinsurongkawong, Waree
AU - Rinsurongkawong, Vadeerat
AU - Lee, Jack
AU - Roth, Jack
AU - Swisher, Stephen
AU - Wistuba, Ignacio
AU - Heymach, John
AU - Wang, Jing
AU - Campbell, Matthew T.
AU - Efstathiou, Eleni
AU - Titus, Mark
AU - Logothetis, Christopher J.
AU - Ho, Thai H.
AU - Zhang, Jianjun
AU - Wang, Linghua
AU - Gao, Jianjun
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-29397-z
DO - 10.1038/s41467-022-29397-z
M3 - Article
C2 - 35379845
AN - SCOPUS:85127516293
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1797
ER -