Open Access
MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
Omar Alhalabi
1
,
Jianfeng Chen
1
,
Yuxue Zhang
1
,
Yang Lu
2
,
Qi Wang
3
,
Sumankalai Ramachandran
1
,
Rebecca S. S. Tidwell
4
,
Guangchun Han
5
,
Xinmiao Yan
5
,
Jieru Meng
1
,
Ruiping Wang Ruiping
5
,
Anh G Hoang
1
,
Wenyi Wang
1
,
Jian Song
1
,
Lidia Lopez
1
,
Alex Andreev Drakhlin
1
,
Arlene Siefker-Radtke
1
,
Zhang Xinqiao
1
,
William F. Benedict
1
,
Amishi Shah
1
,
Jennifer Wang
1
,
Msaouel Pavlos
1
,
Miao Zhang
6
,
Charles C. Guo
6
,
Bogdan Czerniak
6
,
Carmen Behrens
7
,
L. Solis
8
,
Vassiliki Papadimitrakopoulou
7
,
Jeff Lewis
4
,
Waree Rinsurongkawong
4
,
Vadeerat Rinsurongkawong
4
,
J. Jack Lee
4
,
JACK A. ROTH
9
,
Stephen G. Swisher
9
,
Ignacio Wistuba
6
,
John V. Heymach
7
,
Jing Wang
3
,
Matthew T. Campbell
1
,
Eleni Efstathiou
1
,
Mark Titus
1
,
Christopher J. Logothetis
1
,
Thai Ho
10
,
Jianjun Zhang
7
,
Linghua Wang
5, 11
,
Jianjun Gao
1
10
Division of Medical Oncology, Mayo Clinic, Phoenix, USA
|
Publication type: Journal Article
Publication date: 2022-04-04
scimago Q1
wos Q1
SJR: 4.761
CiteScore: 23.4
Impact factor: 15.7
ISSN: 20411723
PubMed ID:
35379845
General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy
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. The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.
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60
Total citations:
60
Citations from 2024:
42
(70%)
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GOST
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Alhalabi O. et al. MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers // Nature Communications. 2022. Vol. 13. No. 1. 1797
GOST all authors (up to 50)
Copy
Alhalabi O., Chen J., Zhang Y., Lu Y., Wang Q., Ramachandran S., Tidwell R. S. S., Han G., Yan X., Meng J., Wang Ruiping R., Hoang A. G., Wang W., Song J., Lopez L., Andreev Drakhlin A., Siefker-Radtke A., Xinqiao Z., Benedict W. F., Shah A., Wang J., Pavlos M., Zhang M., Guo C. C., Czerniak B., Behrens C., Solis L., Papadimitrakopoulou V., Lewis J., Rinsurongkawong W., Rinsurongkawong V., Lee J. J., ROTH J. A., Swisher S. G., Wistuba I., Heymach J. V., Wang J., Campbell M. T., Efstathiou E., Titus M., Logothetis C. J., Ho T., Zhang J., Wang L., Gao J. MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers // Nature Communications. 2022. Vol. 13. No. 1. 1797
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TY - JOUR
DO - 10.1038/s41467-022-29397-z
UR - https://doi.org/10.1038/s41467-022-29397-z
TI - MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
T2 - Nature Communications
AU - Alhalabi, Omar
AU - Chen, Jianfeng
AU - Zhang, Yuxue
AU - Lu, Yang
AU - Wang, Qi
AU - Ramachandran, Sumankalai
AU - Tidwell, Rebecca S. S.
AU - Han, Guangchun
AU - Yan, Xinmiao
AU - Meng, Jieru
AU - Wang Ruiping, Ruiping
AU - Hoang, Anh G
AU - Wang, Wenyi
AU - Song, Jian
AU - Lopez, Lidia
AU - Andreev Drakhlin, Alex
AU - Siefker-Radtke, Arlene
AU - Xinqiao, Zhang
AU - Benedict, William F.
AU - Shah, Amishi
AU - Wang, Jennifer
AU - Pavlos, Msaouel
AU - Zhang, Miao
AU - Guo, Charles C.
AU - Czerniak, Bogdan
AU - Behrens, Carmen
AU - Solis, L.
AU - Papadimitrakopoulou, Vassiliki
AU - Lewis, Jeff
AU - Rinsurongkawong, Waree
AU - Rinsurongkawong, Vadeerat
AU - Lee, J. Jack
AU - ROTH, JACK A.
AU - Swisher, Stephen G.
AU - Wistuba, Ignacio
AU - Heymach, John V.
AU - Wang, Jing
AU - Campbell, Matthew T.
AU - Efstathiou, Eleni
AU - Titus, Mark
AU - Logothetis, Christopher J.
AU - Ho, Thai
AU - Zhang, Jianjun
AU - Wang, Linghua
AU - Gao, Jianjun
PY - 2022
DA - 2022/04/04
PB - Springer Nature
IS - 1
VL - 13
PMID - 35379845
SN - 2041-1723
ER -
Cite this
BibTex (up to 50 authors)
Copy
@article{2022_Alhalabi,
author = {Omar Alhalabi and Jianfeng Chen and Yuxue Zhang and Yang Lu and Qi Wang and Sumankalai Ramachandran and Rebecca S. S. Tidwell and Guangchun Han and Xinmiao Yan and Jieru Meng and Ruiping Wang Ruiping and Anh G Hoang and Wenyi Wang and Jian Song and Lidia Lopez and Alex Andreev Drakhlin and Arlene Siefker-Radtke and Zhang Xinqiao and William F. Benedict and Amishi Shah and Jennifer Wang and Msaouel Pavlos and Miao Zhang and Charles C. Guo and Bogdan Czerniak and Carmen Behrens and L. Solis and Vassiliki Papadimitrakopoulou and Jeff Lewis and Waree Rinsurongkawong and Vadeerat Rinsurongkawong and J. Jack Lee and JACK A. ROTH and Stephen G. Swisher and Ignacio Wistuba and John V. Heymach and Jing Wang and Matthew T. Campbell and Eleni Efstathiou and Mark Titus and Christopher J. Logothetis and Thai Ho and Jianjun Zhang and Linghua Wang and Jianjun Gao},
title = {MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers},
journal = {Nature Communications},
year = {2022},
volume = {13},
publisher = {Springer Nature},
month = {apr},
url = {https://doi.org/10.1038/s41467-022-29397-z},
number = {1},
pages = {1797},
doi = {10.1038/s41467-022-29397-z}
}