Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

Bouchalová, Kateřina; Cizkova, Magdalena; Cwiertka, Karel; Trojanec, Radek; Friedecký, David; Hajdúch, Marián

doi:10.5507/bp.2010.043

Cited by 21 publications

(18 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Human epidermal growth factor receptors (HER) play an important role in proliferation, migration, angiogenesis, and resistance to apoptosis in many cancers (1). HER family is a tyrosine kinase family including four homologous members: HER1, HER2, HER3 and HER4.…”

Section: Introductionmentioning

confidence: 99%

Minimal HER1 and HER2 expressions in CHO and HEK-293 cells cause them appropriate negative cells for HERs-related studies

et al. 2013

View full text Add to dashboard Cite

Background: Understanding of cellular and molecular mechanisms involved in cell/tumor growth and progression has led to molecular-targeted therapy. HER1 and HER2 are two main oncogenic components of HER-receptor family considered as targets for cancer research and therapy. Reliable results of HERrelated research and targeted therapies dependent upon cell line with known HER expression status. But there are no published studies focusing on determination of HER1 and HER2 receptors expression in CHO and HEK-293 cell lines. Materials and Methods: Absolute expressions of HER1 and HER2 in CHO, HEK-293, MDA-MB-468 and SKBR3 cells were evaluated using quantitative real-time PCR. Absolute expression quantification was carried out by serial dilution plasmids harboring HER1 and HER2 to extrapolate standard curve. Results: Real-time PCR amplification was successfully optimized by HER1 and HER2 plasmids with high efficiency and their copy numbers were calculated. The results showed that HER1 was not expressed in CHO and HEK-293 cells but these cells express HER2 up to 9.4 × 10 2 and 1

show abstract

Section: Introductionmentioning

confidence: 99%

Minimal HER1 and HER2 expressions in CHO and HEK-293 cells cause them appropriate negative cells for HERs-related studies

et al. 2013

View full text Add to dashboard Cite

show abstract

“…PTEN modulates lapatinib sensitivity [85], and its loss acts as a marker of poor lapatinib response [58, 86, 87]. In the GE dataset for the BT474 cell-line, no mutation has been detected for PTEN and TP 53 in their corresponding DNA sequences between parental and resistant conditions as reported in the original article associated with this dataset [66], and PTEN expression was up-regulated even in resistant-vs-parental conditions with or without lapatinib (RB-vs-PB, and RT-vs-PB), but the overall mRNA changes were not significant as tested with the one-way ANOVA test ( p - value = 0.264).…”

Section: Resultsmentioning

confidence: 99%

Bayesian model of signal rewiring reveals mechanisms of gene dysregulation in acquired drug resistance in breast cancer

2017

View full text Add to dashboard Cite

Small molecule inhibitors, such as lapatinib, are effective against breast cancer in clinical trials, but tumor cells ultimately acquire resistance to the drug. Maintaining sensitization to drug action is essential for durable growth inhibition. Recently, adaptive reprogramming of signaling circuitry has been identified as a major cause of acquired resistance. We developed a computational framework using a Bayesian statistical approach to model signal rewiring in acquired resistance. We used the p1-model to infer potential aberrant gene-pairs with differential posterior probabilities of appearing in resistant-vs-parental networks. Results were obtained using matched gene expression profiles under resistant and parental conditions. Using two lapatinib-treated ErbB2-positive breast cancer cell-lines: SKBR3 and BT474, our method identified similar dysregulated signaling pathways including EGFR-related pathways as well as other receptor-related pathways, many of which were reported previously as compensatory pathways of EGFR-inhibition via signaling cross-talk. A manual literature survey provided strong evidence that aberrant signaling activities in dysregulated pathways are closely related to acquired resistance in EGFR tyrosine kinase inhibitors. Our approach predicted literature-supported dysregulated pathways complementary to both node-centric (SPIA, DAVID, and GATHER) and edge-centric (ESEA and PAGI) methods. Moreover, by proposing a novel pattern of aberrant signaling called V-structures, we observed that genes were dysregulated in resistant-vs-sensitive conditions when they were involved in the switch of dependencies from targeted to bypass signaling events. A literature survey of some important V-structures suggested they play a role in breast cancer metastasis and/or acquired resistance to EGFR-TKIs, where the mRNA changes of TGFBR2, LEF1 and TP53 in resistant-vs-sensitive conditions were related to the dependency switch from targeted to bypass signaling links. Our results suggest many signaling pathway structures are compromised in acquired resistance, and V-structures of aberrant signaling within/among those pathways may provide further insights into the bypass mechanism of targeted inhibition.

show abstract

“…In 2010 it was approved for use in combination with letrozole for postmenopausal women with hormone receptor positive and HER2-positive metastatic breast cancer based upon encouraging findings from clinical trials [22-24]. Importantly, previous reports highlight that the clinical activity of lapatinib depends primarily upon the HER2 expression status of the tumor; however, the predictive status of EGFR is also currently under investigation [25]. …”

Section: Discussionmentioning

confidence: 99%

“…Recent published findings also demonstrate that PTEN loss and PIK3CA mutations may predict a poor response to single agent lapatinib in breast cancer [25]. As this pathway is often constitutively activated in endometrial adenocarcinomas, which frequently harbor loss of function mutations of PTEN and gain of function mutations in PIK3CA, lack of response to lapatinib may be predictable in the setting of endometrial cancers with this common molecular phenotype [27-29] .…”

Section: Discussionmentioning

confidence: 99%

Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

Leslie

Sill

Lankes

et al. 2012

Gynecologic Oncology

102

View full text Add to dashboard Cite

BACKGROUND A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP Kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC). METHODS Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced. RESULTS Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months. CONCLUSION While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response, suggests that lapatinib may be beneficial in some cases of EC.

show abstract

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

Cited by 21 publications

References 95 publications

Minimal HER1 and HER2 expressions in CHO and HEK-293 cells cause them appropriate negative cells for HERs-related studies

Minimal HER1 and HER2 expressions in CHO and HEK-293 cells cause them appropriate negative cells for HERs-related studies

Bayesian model of signal rewiring reveals mechanisms of gene dysregulation in acquired drug resistance in breast cancer

Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

Contact Info

Product

Resources

About