new mechanism of resistance to herceptin identified

[Lani]

Drug already under developement to reverse

Proc Natl Acad Sci U S A. 2011 Feb 14. [Epub ahead of print]
Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients.
Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, Chandarlapaty S, Serra V, Prat A, Ibrahim YH, Guzmán M, Gili M, RodrÃ*guez O, RodrÃ*guez S, Pérez J, Green SR, Mai S, Rosen N, Hudis C, Baselga J.

Departments of Medical Oncology and Molecular Pathology, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.
Abstract
Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2(+) patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression.

PMID: 21321214

Seliciclib
From Wikipedia, the free encyclopedia
Seliciclib


R-roscovitine (Seliciclib or CYC202) is a trial drug in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel.
Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), leukemia, HIV infection, herpes simplex infection, and the mechanisms of chronic inflammation disorders.
Seliciclib is a 2,6,9-substituted purine analog. Its structure in complex with CDK2 was determined in 1996.[1] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.[2]
[edit]Uses

Seliciclib has been found to produce apoptosis in treated cancerous cells of non-small cell lung cancer (NSCLC) and other cancers. Seliciclib has previously undergone Phase IIa clinical trials, in 240 NSCLC patients as a combined dose with existing first- and second-line treatments.[2][3] In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients.[4] The side-effects reported in Phase I trials of Seliciclib for NSCLC were "nausea, vomiting, transient elevations in serum creatinine and liver function parameters and transient hypokalemia".[3]
Seliciclib is also in clinical trials for B-cell lymphomas, including acute myelogenous leukemia.[citation needed] Seliciclib has been shown to inhibit RNA polymerase II-dependent transcription and down-regulation of myeloid cell leukaemia sequence 1 (Mcl-1). [5][6]
Seliciclib is also a possible anti-viral agent. It causes the death of cells infected with HIV[7][8][9] and preventing the replication of Herpes simplex virus.[10][11]
Seliciclib has been shown in vitro to induce apoptosis in neutrophil granulocytes.[12] If this mechanism turns out to be safe, reliable and efficient in vivo, the drug could improve treatment of chronic inflammation diseases such as cystic fibrosis and arthritis. These are usually treated with glucocorticoids which often have serious side effects.

Great news, Lani, thank you very much

[Ellie F]

Thanks Lani
More good news about things to have in our back pocket. Particularly encouraging is that it's already in trials.

Ellie

[Trish]

Thank you Lani-hopefully another piece of the puzzle
Trish

[Lani]

more on cyclacel drug:

Cyclacel's CYC065 CDK inhibitor demonstrates potential against breast cancer resistant to trastuzumab
18. February 2011 04:26

Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) (Cyclacel or the Company), today announced the publication of preclinical data in the Proceedings of the National Academy of Sciences (PNAS), demonstrating that cyclin E plays a major role in making Human Epidermal growth factor Receptor 2 positive (HER2+) breast cancer resistant to trastuzumab (Herceptin®), a widely used medicine for breast cancer patients who test positive for HER2. The publication provides a rationale for exploring Cyclacel's orally available CDK inhibitors in this patient population.

Elevated expression levels of cyclin E in HER2+ patients treated with trastuzumab resulted in a reduced rate of clinical benefit and lower survival compared with patients whose cancers did not overexpress cyclin E. Treatment of HER2+ breast cancer cells resistant to trastuzumab with CYC065, Cyclacel's cyclin-dependent kinase (CDK) inhibitor, blocked CDK2/cyclin E activity, dramatically slowed tumor growth and killed resistant breast cancer cells.

"For over a decade Cyclacel has emerged as a leader in the study of cell cycle biology and the identification of novel anticancer drugs that exploit mechanisms of cell cycle control. We are excited about CYC065's promising activity in breast cancer resistant to trastuzumab, one of the mainstay therapies for early-stage breast cancer," said Spiro Rombotis, Cyclacel's President & Chief Executive Officer. "The publication by a leading breast cancer group extends and supports previous reports showing that targeting CDK2/cyclin E with Cyclacel's novel CDK inhibitors, seliciclib and CYC065, can kill cancer cells, such as breast and lung cancer, that fail to respond to current standards of care."




The CDK2 enzyme and its partner protein, cyclin E, have been extensively investigated as therapeutic targets in light of their frequent deregulation in breast cancers with a poor prognosis. In the PNAS article titled "Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 positive breast cancer patients," investigators from Massachusetts General Hospital Cancer Center, (Boston, MA), Vall d'Hebron University Hospital (Barcelona, Spain), Memorial Sloan-Kettering Cancer Center (New York, NY) and Manitoba Institute of Cell Biology (Winnipeg, Canada) performed a genome-wide analysis to pinpoint causes of resistance in HER2+ breast cancer. Their analysis identified cyclin E as the common genetic signature of resistance to trastuzumab in HER2+ breast cancer cells. Cyclacel's CYC065, a second generation CDK inhibitor, was found to be effective in killing trastuzumab-resistant breast cancer cells in vitro and in vivo. The mechanism of action of CYC065 included inhibition of CDK2/cyclin E, cell cycle arrest and induction of cell death by apoptosis.

"We have determined that breast cancer cells resistant to therapeutic agents targeting HER2 are highly sensitive to CDK inhibition by CYC065," said Maurizio Scaltriti, Ph.D., research scientist from the Division of Hematology and Oncology of the Massachusetts General Hospital Cancer Center, and first author of the manuscript. "Amplification and overexpression of cyclin E is a mechanism by which breast cancer cells develop resistance to trastuzumab. Modulations of cyclin E levels by genetic means result in different sensitivity towards the anti-HER2 agent. Cyclin E overexpressing, trastuzumab-resistant cells have higher CDK2 activity and are more sensitive to pharmacological inhibition by inhibitors, such as seliciclib or its more potent derivative, CYC065. CYC065 has promising in vivo activity in xenograft models of resistant cells, and this activity appears to be enhanced by the addition of trastuzumab."

An estimated 15 to 20 percent of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product, which results in an aggressive tumor phenotype and reduced survival. HER2 targeted agents such as trastuzumab are highly effective in adjuvant and metastatic breast cancer. However clinical effectiveness is strongly diminished by primary or acquired resistance. Identification and targeting the causative mechanisms for such resistance, such as CDK2/cyclin E activation, may have a significant impact in improving therapeutic outcomes in HER2+ breast cancer patients. In a small retrospective study the authors of the PNAS article demonstrated that approximately 35% of HER2+ breast tumors had overexpressed/amplified cyclin E and this correlated with decreased sensitivity to trastuzumab. Frequently, cyclin E overexpression was not associated with other mechanisms of trastuzumab resistance underscoring the potential contribution that CDK inhibitors, such as CYC065 and seliciclib, may confer in this patient population.

Cyclacel continues to collaborate with the scientific team led by Jose Baselga, M.D., Ph.D., Chief of the Division of Hematology/Oncology and Associate Director of the Massachusetts General Hospital Cancer Center in order to further validate the therapeutic potential of CDK inhibitors in a cyclin E-mediated, trastuzumab-resistant patient population.

SOURCE Cyclacel Pharmaceuticals, Inc.