CHICAGO – Because of limited treatment options after the failure of initial therapy, clinical management of acute myeloid leukemia remains a challenge for clinicians.
One area of significant interest, according to a report in the journal Blood, has been therapeutic targeting of the mammalian target of rapamycin (mTOR) pathway. A study led by researchers from Northwestern University and the Jesse Brown VAMC, both in Chicago, explained that mTOR signaling plays a central role in aberrant leukemia cell proliferation and survival. In fact, about 60% of AML patients possess mutations resulting in the activation of the mTOR pathway.1
The authors noted that, despite the anticipated therapeutic potential of inhibition of mTOR, a serine/threonine kinase that plays a central role in the regulation of cellular processes, including protein synthesis, metabolism, and growth, investigation of small molecules that inhibit mTORC1 in AML has yielded limited clinical responses. They pointed out that a number of factors limit the efficacy of mTORC1 inhibition in leukemia, including the presence of negative regulatory feedback loops and redundant pathways that confer a survival advantage.
“This has led to the development of catalytic mTOR inhibitors, which inhibit both mTORC1 and mTORC2, and combinatorial strategies using inhibitors that target PI3K, autophagy, and MAPK pathways,” the study noted. “However, none of these approaches have been approved for clinical use thus far, in part, due to limited responses or dose limiting toxicity. Therefore, it is crucial to discover new elements and effectors of the mTOR pathway that could be therapeutically targeted.”
In an effort to improve understanding of factors that contribute to mTOR signaling activation and identify novel therapeutic targets, the researchers searched for unique interactors of mTOR complexes through proteomics analyses. They identified cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8.
“Our studies demonstrate that CDK9 is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to RAPTOR and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to RICTOR, SIN1, and mLST8, forming CTORC2, and controls messenger RNA (mRNA) translation through phosphorylation of LARP1 and rpS6,” the authors wrote. “Pharmacological targeting of CTORC complexes results in suppression of growth of primitive human AML progenitors in vitro and elicits strong antileukemic responses in AML xenografts in vivo.”
The authors concluded that CDK9 appears to form two distinct cellular complexes that play key roles in mRNA transcription and translation of mitogenic genes and leukemogenesis, adding, “Efforts to therapeutically target these 2 complexes may ultimately lead to advances in the treatment of AML and possibly other malignancies.”
- Beauchamp EM, Abedin SM, Radecki SG, et al. Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. 2019;133(11):1171-1185. doi:10.1182/blood-2018-08-870089
