04 May 2022

New therapeutic targets have been identified for adult T-cell leukaemia/lymphoma (ATLL) through whole genome screening, researchers have announced.

Dr Masao Nakagawa, of Hokkaido University in Japan, and colleagues carried out genome-wide screening with CRISPR technology. They found six genes – CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB – which appear necessary for ATLL cells to survive and grow.

Next, they tested an inhibitor of CDK6 called palbociclib. This drug is already used for the treatment of HR-positive and HER2-negative breast cancer.

“Palbociclib induced cell cycle arrest and apoptosis in ATLL models,” the researchers reported in the journal Blood. The sensitivity of ATLL cell lines to palbociclib appeared to depend on the mutation status of the TP53 gene; cell lines carrying mutations that inactivate or remove p53 protein were the most resistant.

The gene screen also highlighted the dependence of ATLL cells on mTORC1 signalling. A combination of palbociclib and mTORC1 inhibitors killed ATLL cell lines – and primary samples donated by patients in mice – more effectively than either drug alone.

They conclude: “This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.”

Dr Nakagawa commented: “Our study reveals CDK6 as an attractive target for treating adult T-cell leukaemia/lymphoma.

“However, we also discovered that loss of tumour protein p53 function in some adult T-cell leukaemia/lymphoma cell lines leads to resistance to the CDK6 inhibitor, palbociclib.

“Given this finding, researchers should consider the status of tumour protein p53 in future clinical trials of palbociclib in adult T-cell leukaemia/lymphoma.”

Source: Ishio T, Kumar S, Shimono J, Daenthanasanmak A, Dubois S, Lin Y, Bryant B, Petrus MN, Bachy E, Huang DW, Yang Y, Green PL, Hasegawa H, Maeda M, Goto H, Endo T, Yokota T, Hatanaka KC, Hatanaka Y, Tanaka S, Matsuno Y, Yang Y, Hashino S, Teshima T, Waldmann TA, Staudt LM, Nakagawa M. (2022) “Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma.” Blood, doi: 10.1182/blood.2021012734

Link: https://ashpublications.org/blood/article-abstract/139/10/1541/482776/Genome-wide-CRISPR-screen-identifies-CDK6-as-a

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