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.