RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low as opposed to high tumoral RRM1 expression when treated with gemcitabine-containing chemotherapy. However, the principal hypothesis that intratumoral levels of gene expression are associated with disease response has not been addressed.
We constructed genetically modified lung cancer cell lines with increased and decreased RRM1 expression to investigate the in vitro 50% inhibitory concentration (IC50) for gemcitabine, cisplatin, and carboplatin. A prospective phase II clinical trial in patients with locally advanced non-small-cell lung cancer was conducted with pretreatment tumor collection for determination of RRM1 and ERCC1 expression by real-time reverse transcriptase polymerase chain reaction. The levels of gene expression were correlated with tumor response after two cycles of gemcitabine and carboplatin.
In cell lines with a genetically engineered 15-fold RRM1 expression range, the gemcitabine IC50 had a 100-fold range, and the cisplatin and carboplatin IC50 had a two-fold range. They were highest in constructs with high RRM1 expression. In the prospective clinical trial, RRM1 expression was significantly (P = .002) and inversely correlated (r = -0.498) with disease response. ERCC1 expression showed a similar trend (P = .099).
The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.
"An increased level of RRM1 enables cancer cells to more efficiently repair DNA damage caused by chemotherapy, resulting in resistance to gemcitabine. In fact, RRM1 is believed to be the predominant cellular determinant of the efficacy of the nucleoside analogue gemcitabine . For instance, a meta-analysis of Gong et al.  has shown that RRM1-low or RRM1-negative advanced NSCLC is associated with a higher response rate to gemcitabine-containing regimen and a better prognosis. "
[Show abstract][Hide abstract] ABSTRACT: Purpose
To assess the therapeutic value of biomarker-guided chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).MethodsEighty-five NSCLC patients at stage IIIb or IV were divided into two groups based on the feasibility of biomarker analysis. Group A included patients with biomarker data (n = 41); Group B were patients without biomarker results (n = 44). Tumor samples obtained by fiberoptic bronchoscopy and computerized tomography-guided needle biopsy were analyzed by immunohistochemistry for intratumoral level of excision repair cross-complementing gene 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and β-tubulin III. Chemotherapy regimens in Group A were determined according to the status of molecular signatures, whereas a standard gemcitabine plus cisplatin regimen was used for Group B. Tumor response, patient survival, and adverse effects were monitored for both groups.ResultsThe overall response rate, defined as complete response plus partial response, was 56.1 % for Group A, significantly higher than that in Group B (31.8 %; P = 0.024). The median progression-free survival (PFS) time was 5.2 months for Group A, significantly longer than that of Group B (4.1 months; P = 0.026). The 1-year survival rate of Group A was 65.9 %, significantly higher than that of Group B (40.9 %; P = 0.021), whereas the median overall survival times were 13.5 versus 12.5 months for Groups A and B, respectively (P = 0.483). The adverse effects in the two groups were essentially the same.ConclusionsBiomarker-tailored chemotherapy based on ERCC1, RRM1, and β-tubulin III expression showed significantly increased response rate, median PFS time, and 1-year survival rate in patients with NSCLC.
Cancer Chemotherapy and Pharmacology 08/2014; 74(4). DOI:10.1007/s00280-014-2513-x · 2.77 Impact Factor
"However, a significant inhibition of RRM1 was seen when LY2835219 was combined with gemcitabine. In vitro and in vivo chemosensitivity to gemcitabine strongly correlates to RRM1 expression [45, 46], consistent with the modulation of RRM1 seen for LY2835219 and gemcitabine in our experiments. CDK4/6 can phosphorylate substrates other than Rb, such as FOXM1 and E2F1 [10, 11], which may explain the inhibition of RRM1 and the absence of inhibition of p-Rb and a cell cycle arrest. "
[Show abstract][Hide abstract] ABSTRACT: The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.
Electronic supplementary material
The online version of this article (doi:10.1007/s10637-014-0120-7) contains supplementary material, which is available to authorized users.
Investigational New Drugs 06/2014; 32(5). DOI:10.1007/s10637-014-0120-7 · 2.92 Impact Factor
"Expression of Multidrug resistance-associated protein 1 (MRP-1) correlates to doxorubicin sensitivity . Expression of Excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1) and Ribonucleotide reductase M1 (RRM1) correlates to treatment effect of gemcitabine or carboplatin , , , . Thymidylate synthase (TS) is the main target for pemetrexed  and a low expression of TS has been correlated to a higher overall survival of MM patients treated with pemetrexed and a platinum agent , . "
[Show abstract][Hide abstract] ABSTRACT: Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit.
We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers.
As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect.
The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.
PLoS ONE 06/2013; 8(6):e65903. DOI:10.1371/journal.pone.0065903 · 3.23 Impact Factor
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