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Lapatinib resistance

Spencer S Watson, Mark Dane, Koei Chin, Zuzana Tatarova, Moqing Liu, Tiera Liby, Wallace Thompson, Rebecca Smith, Michel Nederlof, Elmar Bucher, David Kilburn, Matthew Whitman, Damir Sudar, Gordon B Mills, Laura M Heiser, Oliver Jonas, Joe W Gray, James E Korkola
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib...
February 21, 2018: Cell Systems
Lunming Liu, Weifeng Shen, Zhihui Zhu, Jinxiong Lin, Qingxia Fang, Yeping Ruan, Huajun Zhao
Fulvestrant is the FDA-approved "pure anti-estrogen" agent for malignant breast cancer therapy. But endocrine resistance causes drug failure. A new approach is desired for fulvestrant-resistant breast cancer (FRBC) therapy. This study aims to find an effective approach to inhibit FRBC for patients with advanced breast cancer. MTT assay was first performed to detect the effect of inhibitors of c-ABL (imatinib) and EGFR (lapatinib) on FRBC cells. Microarray analysis was carried out to identify microRNA which is significantly changed between parental and FRBC cells...
March 6, 2018: Biochemical and Biophysical Research Communications
Konstantinos V Floros, Timothy L Lochmann, Bin Hu, Carles Monterrubio, Mark T Hughes, Jason D Wells, Cristina Bernadó Morales, Maninderjit S Ghotra, Carlotta Costa, Andrew J Souers, Sosipatros A Boikos, Joel D Leverson, Ming Tan, Violeta Serra, Jennifer E Koblinski, Joaquin Arribas, Aleix Prat, Laia Paré, Todd W Miller, Mikhail G Dozmorov, Hisashi Harada, Brad E Windle, Maurizio Scaltriti, Anthony C Faber
HER2 ( ERBB2 ) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR -mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment...
February 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Teruo Yamauchi, Jose Rodrigo Espinosa Fernandez, Chiyo K Imamura, Hideko Yamauchi, Hiromitsu Jinno, Maiko Takahashi, Yuko Kitagawa, Seigo Nakamura, Bora Lim, Savitri Krishnamurthy, James M Reuben, Diane Liu, Debasish Tripathy, Helen Chen, Naoko Takebe, Hideyuki Saya, Naoto T Ueno
Chemotherapy has been reported to increase the proportion of cancer stem cells (CSCs) and to promote epithelial-mesenchymal transition (EMT) phenotype changes. Anti-HER2 therapy may provide a strategy for eliminating CSC and EMT, which contribute to therapeutic resistance. No study has determined the changes in the quantity or characteristics of CSCs or circulating tumor cells (CTCs) with EMT phenotype during preoperative anti-HER2 therapy, and whether these changes correlate to response to dual anti-HER2 therapy...
January 23, 2018: Oncotarget
Jacqueline R Ha, Ryuhjin Ahn, Harvey W Smith, Valerie Sabourin, Steven Hėbert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia Kleinman, William J Muller, Josie Ursini-Siegel
The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA (SHC1) is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTKs), such as ErbB2, engage the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling...
February 16, 2018: Molecular Cancer Research: MCR
Peng Jiang, Winston Lee, Xujuan Li, Carl Johnson, Jun S Liu, Myles Brown, Jon Christopher Aster, X Shirley Liu
Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers...
February 6, 2018: Cell Systems
S T Kim, K C Banks, E Pectasides, S Y Kim, K Kim, R B Lanman, A Talasaz, J An, M G Choi, J H Lee, T S Sohn, J M Bae, S Kim, S H Park, J O Park, Y S Park, H Y Lim, N K D Kim, W Park, H Lee, A J Bass, K Kim, W K Kang, J Lee
Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and Methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer (AGC). A parallel biomarker study was conducted by simultaneously performing immunohistochemistry (IHC) and next-generation sequencing with tumor and blood samples...
February 2, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Sharad Verma, Sukriti Goyal, Anchala Kumari, Aditi Singh, Salma Jamal, Abhinav Grover
HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant...
2018: PloS One
Catherine Terret, Chiara Russo
As its incidence increases with age, breast cancer in elderly patients takes on a growing importance in clinical oncology practice. Management decisions are challenging because there is a lack of high-quality evidence in this heterogeneous population. Epidemiological studies have shown that breast cancer mortality does not decrease substantially in the older population compared with younger adults. Recent data suggest a phenotype somewhat different from that of younger patients, also confirmed at the molecular level...
January 31, 2018: Drugs & Aging
Erika Martinelli, Teresa Troiani, Vincenzo Sforza, Giulia Martini, Claudia Cardone, Pietro Paolo Vitiello, Davide Ciardiello, Anna Maria Rachiglio, Nicola Normanno, Andrea Sartore-Bianchi, Silvia Marsoni, Alberto Bardelli, Salvatore Siena, Fortunato Ciardiello
Background: Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients...
2018: ESMO Open
Lu Liu, Liang Zhong, Yi Zhao, Min Chen, Shifei Yao, Lianwen Li, Chunlan Xiao, Zhiling Shan, Liugen Gan, Ting Xu, Beizhong Liu
Acute promyelocytic leukemia (APL), characterized by the presence of the promyelocytic leukemia (PML)-retinoic acid α receptor (RARα) fusion protein, responds to treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, drug resistance and side effects restrict the application of these reagents. Hence, the development of novel therapeutic drugs for APL treatment is critical. Lapatinib, a small-molecule tyrosine kinase inhibitor, has been used in the treatment of different tumors. However, it is unclear whether lapatinib exerts antitumor effects on APL...
January 2018: Oncology Letters
Tsuyoshi Karibe, Tomoki Imaoka, Koji Abe, Osamu Ando
To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selectiveBCRP inhibition, in addition to several well-known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole...
January 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Thomas A Werfel, Shan Wang, Meredith A Jackson, Taylor E Kavanaugh, Meghan Morrison Joly, Linus Lee, Donna J Hicks, Violeta Sanchez, Paula I Gonzalez-Ericsson, Kameron V Kilchrist, Somtochukwu C Dimobi, Samantha M Sarett, Dana M Brantley-Sieders, Rebecca S Cook, Craig Duvall
Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date...
January 22, 2018: Cancer Research
Bian Li, Wang Tao, Zhang Shao-Hua, Q U Ze-Rui, Jin Fu-Quan, L I Fan, Jiang Ze-Fei
In clinical practice, one subgroup patients of breast cancer might have developed resistance to multi-anti-HER2 targeted drugs(trastuzumab,lapatinib and/or T-DM1) and can not benefit from the anti-HER2 targeted therapy continuously. We attempt to change the next therapic way for these patients.Two patients with metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy were treated with pembrolizumab(2mg/Kg, day1) plus albumin-bound paclitaxel(125mg/m2, day1,8) every 3 weeks.CT evaluation and HER2 ECD test were performed every 2 cycles...
January 15, 2018: Cancer Biology & Therapy
Marwan G Fakih
Human epidermal growth factor 2 (HER2) amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti-epidermal growth factor receptor resistance and sensitivity to dual HER2 targeting. Although clinical trials have reported activity for trastuzumab/pertuzumab and trastuzumab/lapatinib combinations, there are no reports on lapatinib plus trastuzumab activity after resistance to trastuzumab plus pertuzumab. Presented are three cases of HER2 amplified colorectal cancer that developed acquired refractoriness to trastuzumab pertuzumab with subsequent clinical benefit to lapatinib plus trastuzumab, highlighting the potential for HER2 tyrosine kinase inhibition plus trastuzumab in overcoming trastuzumab/pertuzumab resistance...
January 12, 2018: Oncologist
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
Gerjon J Ikink, Mandy Boer, Elvira R M Bakker, Annabel Vendel-Zwaagstra, Chris Klijn, Jelle Ten Hoeve, Jos Jonkers, Lodewyk F Wessels, John Hilkens
Personalized medicine for cancer patients requires a deep understanding of the underlying genetics that drive cancer and the subsequent identification of predictive biomarkers. To discover new genes and pathways contributing to oncogenesis and therapy resistance in HER2+ breast cancer, we performed Mouse Mammary Tumor Virus (MMTV)-induced insertional mutagenesis screens in ErbB2/cNeu-transgenic mouse models. The screens revealed 34 common integration sites (CIS) in mammary tumors of MMTV-infected mice, highlighting loci with multiple independent MMTV integrations in which potential oncogenes are activated, most of which had never been reported as MMTV CIS...
January 12, 2018: Oncogene
Nancy D Ebelt, Tamer S Kaoud, Ramakrishna Edupuganti, Sabrina Van Ravenstein, Kevin N Dalby, Carla L Van Den Berg
Triple negative breast cancers (TNBC) have poor prognosis compared to other breast cancer subtypes and represent 15-20% of breast cancers diagnosed. Unique targets and new molecularly-targeted therapies are urgently needed for this subtype. Despite high expression of Epidermal Growth Factor Receptor, inhibitors such as lapatinib have not shown therapeutic efficacy in TNBC patients. Herein, we report that treatment with the covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death, while these compounds as single agents have little effect...
December 1, 2017: Oncotarget
Marcelo D Vilela, William T Longstreth, Hugo As Pedrosa, Gabriel Ob Gil, Juliano M Duarte, Marco Antonio D Filho
BACKGROUND: Trastuzumab emtansine, an antibody-drug conjugate commonly abbreviated as T-DM1, is accepted as an effective therapy for trastuzumab-resistant metastatic HER2-positive breast cancer. T-DM1 significantly increases progression-free and overall survival when compared to lapatinib plus capecitabine in patients with HER2-positive breast cancer previously treated with trastuzumab and a taxane. Among the common side effects related to T-DM1, thrombocytopenia and mucosal hemorrhage are seen, although they are infrequently judged to be clinically significant...
December 20, 2017: World Neurosurgery
Rebecca Madden, Sam Kosari, Gregory M Peterson, Nasser Bagheri, Jackson Thomas
OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which accounts for 20 - 25% of cases of breast cancers, is highly aggressive. Due to cardiotoxicity and increasing resistance associated with trastuzumab, the first-line treatment, there is a need for effective second-line therapies in treating HER2-positive breast cancer. In this context, there has been increasing interest in the combination of lapatinib plus capecitabine. The aim of this systematic review was to assess the efficacy of lapatinib plus capecitabine for HER2-positive breast cancer after progression with trastuzumab therapy, in comparison with capecitabine monotherapy and other agents such as vinorelbine and trastuzumab emtansine...
February 2018: International Journal of Clinical Pharmacology and Therapeutics
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