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Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.


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