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Lenalidomide targets CSNK1A1 in myelodysplastic syndrome with del(5q)
SAN FRANCISCO — Lenalidomide appears to be effective in myelodysplastic syndrome with the deletion of chromosome 5q through the ubiquitination and degradation of the casein kinase 1A1, according to study results presented here.
“Lenalidomide is a highly effective treatment for both multiple myeloma and myelodysplastic syndrome with del(5q),” Emma C. Fink, an MD/PhD student in the division of hematology at Brigham and Women’s Hospital, said during the plenary session. “Lenalidomide is particularly striking in that it specifically targets the del(5q) clone, leading to a complete cytogenetic response in up to 50% of patients with del(5q) myelodysplastic syndrome. Lenalidomide is a derivative of the infamous sedative thalidomide (Thalomid, Celgene), whose use in pregnant women led to the birth of more than 10,000 infants with limb malformations and other disabilities.”
Fink and colleagues previously demonstrated that lenalidomide (Revlimid, Celgene) activates the CRBN-CRL4 E3 ubiquitin ligase leading to the ubiquitination of IKZF1 and IKZF3 in multiple myeloma. In the current analysis, researchers sought to identify a therapeutic target in myelodysplastic syndrome with the deletion of chromosome 5q (del[5q]).
Researchers found casein kinase 1A1 (CSNK1A1) — which is encoded in the del(5q) commonly deleted region — had increased ubiquitination and decreased protein levels after lenalidomide treatment in the myeloid cell line KG-1. Human cell line studies further suggested that lenalidomide treatment increased CSNK1A1 ubiquitination and decreased CSNK1A1 protein levels according to dosage.
Because lenalidomide led to the co-immunoprecipitation of CSNK1A1 with CRBN, researchers determined CSNK1A1 directly interacted with the substrate adapter for the ubiquitin ligase.
Researchers then sought to evaluate how CSNK1A1 degradation may be linked to lenalidomide’s ability to target cells with del(5q). They found haploinsufficiency for CSNK1A1 might increase lenalidomide sensitivity in del(5q) cells because short hairpin RNA-mediated knockdown of CSNK1A1 was associated with lenalidomide sensitivity of primary human CD34+ cells.
In a CSNK1A1 conditional knockout model, murine Ba/F3 cells that overexpressed human CRBN degraded CSNK1A1 with lenalidomide.
Further, CSNK1A1+/- cells that expressed human CRBN depleted over time compared with wild-type controls when treated with lenalidomide. Researchers also found the sensitivity of CSNK1A1+/- cells to lenalidomide was associated with induction of p21 and was rescued by the heterozygous deletion of p53.
“We identified a single non-conservative amino acid in mouse and human CRBN that determines lenalidomide response,” Fink said. “This subtle mutation may have contributed to the approval thalidomide for use in humans, and the resulting human tragedy. Understanding this species difference may facilitate the development of improved preclinical models for the settings of these drugs in vivo. Taken together, our study reinforces the important of haploinsufficient genes and both the pathogenesis and treatment of disease. It also suggests that these drugs, with their novel mechanism of targeted degradation of specific proteins, may ultimately be applicable to a wide variety of clinical conditions.”
For more information:
Fink EC. Abstract #4. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.
Disclosure: One researcher reports research funded from Celgene and a consultant role with Genoptix.
Perspective
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In the current study, the investigators demonstrated that lenalidomide utilized a similar mechanism to deplete CSNK1A1 in myeloid cells. The observation that a similar mechanism is involved in two hematopoietic lineages builds confidence that this is a relevant mechanism of action for this class of drugs. CSNK1A1 is a particularly compelling target for two reasons. First, this gene is located on the long arm of chromosome 5, which is frequently deleted in patients with myelodysplastic syndrome. Loss of a single copy of CSNK1A1 in these patients leads to haploinsufficiency, which provides an explanation for the previously observed sensitivity of del(5q) cells to lenalidomide. Second, these investigators have previously shown that CSNK1A1 is a potential therapeutic target in a mouse model of acute myeloid leukemia. It should be noted that the “IMiD” class of drugs have pleiotropic effects in patients and this mechanism of action may not account for all of them.
This study has broad implications for future research. Now that we have a handle on the mechanism of action for this class of drugs, this can be used as a platform to screen and identify other compounds that are perhaps more potent and better tolerated. Second, this novel mechanism of action could provide a strategy to deplete factors critical for the survival of other types of cancer cells that were previously viewed as “undruggable.” Finally, the investigators demonstrated that a single amino acid substitution in CRBN explains why human cells respond to this class of drug and mouse cells do not. This may account for the failure to identify the teratogenic effects of this class of drugs in previous rodent studies and provides a path forward to screen molecules and avoid this potential toxicity in the future.
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Importantly, this study validates the concept of targeting vulnerabilities in cancer due to haploinsufficiency, also highly relevant to solid tumors. The study informs studies on drug resistance, as well as the rationale design of more effective immunomodulatory drugs. In this regard, the novel mouse models described in this study will be powerful tools for preclinical studies. Finally, the novel mechanisms of lenalidomide’s activity raises the intriguing issue of whether E3 ubiquitin ligases can be harassed to destroy targets that were previously deemed “undruggable.”