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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/27913578/characterization-of-egfr-t790m-l792f-and-c797s-mutations-as-mechanisms-of-acquired-resistance-to-afatinib-in-lung-cancer
#1
Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib...
December 2, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27903753/a-novel-lsd1-inhibitor-t-3775440-disrupts-gfi1b-containing-complex-leading-to-transdifferentiation-and-impaired-growth-of-aml-cells
#2
Yoshinori Ishikawa, Kanae Gamo, Masato Yabuki, Shinji Takagi, Kosei Toyoshima, Kazuhide Nakayama, Akiko Nakayama, Megumi Morimoto, Hitoshi Miyashita, Ryo Dairiki, Yukiko Hikichi, Naoki Tomita, Daisuke Tomita, Shinichi Imamura, Misa Iwatani, Yusuke Kamada, Satoru Matsumoto, Ryujiro Hara, Toshiyuki Nomura, Ken Tsuchida, Kazuhide Nakamura
Dysregulation of the histone demethylase LSD1, also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here we describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27903752/hexim1-as-a-robust-pharmacodynamic-marker-for-monitoring-target-engagement-of-bet-family-bromodomain-inhibitors-in-tumors-and-surrogate-tissues
#3
Xiaoyu Lin, Xiaoli Huang, Tamar Uziel, Paul Hessler, Daniel H Albert, Lisa A Roberts-Rapp, Keith F McDaniel, Warren M Kati, Yu Shen
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic (PD) markers such as c-Myc, BRD2, etc. failed to detect PD marker responses in AML patients treated at active dose and those with clinical responses. Here we report the identification and characterization of HEXIM1 and other genes as robust PD markers for BET inhibitors...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27903751/microdose-induced-drug-dna-adducts-as-biomarkers-of-chemotherapy-resistance-in-humans-and-mice
#4
Maike Zimmermann, Si-Si Wang, Hongyong Zhang, Tzu-Yin Lin, Michael Malfatti, Kurt Haack, Ted Ognibene, Hongyuan Yang, Susan Airhart, Kenneth W Turteltaub, George D Cimino, Clifford G Tepper, Alexandra Drakaki, Karim Chamie, Ralph de Vere White, Chong-Xian Pan, Paul T Henderson
We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry (AMS) in blood and tumor samples collected within 24 hours, and compared to subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27903750/nuclear-export-of-ubiquitinated-proteins-determines-the-sensitivity-of-colorectal-cancer-to-proteasome-inhibitor
#5
Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q X Li, Long Cui, Yili Yang
Although proteasome inhibitors such as Bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a mono-therapy for solid tumors, including colorectal cancer. We found in the present study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of Bortezomib on colon cancer cells containing wild type p53, which underwent G2/M cell cycle block and apoptosis...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27837031/pharmacological-inhibition-of-myocardin-related-transcription-factor-pathway-blocks-lung-metastases-of-rhoc-overexpressing-melanoma
#6
Andrew J Haak, Kathryn M Appleton, Erika M Lisabeth, Sean Misek, Yajing Ji, Susan M Wade, Jessica L Bell, Cheryl E Rockwell, Merlin Airik, Melanie A Krook, Scott D Larsen, Monique E Verhaegen, Elizabeth R Lawlor, Richard R Neubig
Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity...
November 11, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27837030/clinicopathological-and-functional-significance-of-recql1-helicase-in-sporadic-breast-cancers
#7
Arvind Arora, Swetha Parvathaneni, Mohammed A Aleskandarany, Devika Agarwal, Reem Ali, Tarek Ma Abdel-Fatah, Andrew R Green, Graham R Ball, Emad A Rakha, Ian O Ellis, Sudha Sharma, Srinivasan Madhusudan
RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germ-line RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathological significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level [METABRIC cohort, n=1977] and at the protein level [cohort 1, n=897; cohort 2, n= 252; cohort 3 (BRCA-germline deficient), n=74]...
November 11, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27837029/digitalis-like-compounds-facilitate-non-medullary-thyroid-cancer-redifferentiation-through-intracellular-ca2-fos-and-autophagy-dependent-pathways
#8
Marika H Tesselaar, Thomas Crezee, Herman G Swarts, Danny Gerrits, Otto C Boerman, Jan B Koenderink, Hendrik G Stunnenberg, Mihai G Netea, Jan Wa Smit, Romana T Netea-Maier, Theo S Plantinga
Up to 20-30% of patients with metastatic non-medullary thyroid cancer have persistent or recurrent disease resulting from tumour dedifferentiation. Tumour redifferentiation to restore sensitivity to radioactive iodide (RAI) therapy is considered a promising strategy to overcome RAI resistance. Autophagy has emerged as an important mechanism in cancer dedifferentiation. Here, we demonstrate the therapeutic potential of autophagy activators for redifferentiation of thyroid cancer cell lines. Five autophagy activating compounds, all known as digitalis-like compounds, restored hNIS expression and iodide uptake in TC cell lines...
November 11, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27837028/asp5878-a-novel-inhibitor-of-fgfr-1-2-3-and-4-inhibits-the-growth-of-fgf19-expressing-hepatocellular-carcinoma
#9
Takashi Futami, Hidetsugu Okada, Rumi Kihara, Tatsuya Kawase, Ayako Nakayama, Tomoyuki Suzuki, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu
Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2...
November 11, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27811012/her2-status-in-advanced-or-metastatic-gastric-esophageal-or-gastro-esophageal-adenocarcinoma-for-entry-to-the-trio-013-logic-trial-of-lapatinib
#10
Michael F Press, Catherine E Ellis, Robert C Gagnon, Tobias J Grob, Marc Buyse, Ivonne Villalobos, Zhiyong Liang, Shafei Wu, Yung-Jue Bang, Shu-Kui Qin, Hyun Cheol Chung, Jianming Xu, Joon Oh Park, Krzysztof Jeziorski, Karen Afenjar, Yanling Ma, Monica C Estrada, Douglas M Robinson, Stefan J Scherer, Guido Sauter, J Randolph Hecht, Dennis J Slamon
HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2-amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx fluorescence in situ hybridization (FISH) and HercepTest immunohistochemistry assays...
November 3, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27811011/mena-confers-resistance-to-paclitaxel-in-triple-negative-breast-cancer
#11
Madeleine J Oudin, Lucie Barbier, Claudia Schäfer, Tatsiana Kosciuk, Miles A Miller, Sangyoon Han, Oliver Jonas, Douglas A Lauffenburger, Frank B Gertler
Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA, particularly its invasive isoform, MENAINV, are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human breast cancer patients. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics...
November 3, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27811010/dual-inhibition-of-mek-and-pi3k-akt-rescues-cancer-cachexia-through-both-tumor-extrinsic-and-intrinsic-activities
#12
Erin E Talbert, Jennifer Yang, Thomas A Mace, Matthew R Farren, Alton B Farris, Gregory S Young, Omar Elnaggar, Zheng Che, Cynthia D Timmers, Priyani Rajasekera, Jennifer M Maskarinec, Mark Bloomston, Tanios Bekaii-Saab, Denis C Guttridge, Gregory B Lesinski
Involuntary weight loss, a part of the cachexia syndrome, is a debilitating co-morbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses, but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anti-cachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK½ inhibitor MEK162...
November 3, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27811009/penfluridol-represses-integrin-expression-in-breast-cancer-through-induction-of-reactive-oxygen-species-and-downregulation-of-sp-transcription-factors
#13
Erik Hedrick, Xi Li, Stephen Safe
It was recently demonstrated the penfluridol inhibited breast tumor growth and metastasis and this was associated with downregulation of α6- and β4-integrins. In this study, we observed the penfluridol induced reactive oxygen species (ROS) and this was the primary mechanism of action. Penfluridol-mediated growth inhibition, induction of apoptosis, and inhibition breast cancer cell migration was attenuated after cotreatment with glutathione (GSH). Penfluridol also downregulated Sp transcription factors Sp1, Sp3 and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated microRNAs (miR-27a and miR-20a/miR-17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4...
November 3, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27799356/simvastatin-induced-apoptosis-in-osteosarcoma-cells-a-key-role-of-rhoa-ampk-p38-mapk-signaling-in-antitumor-activity
#14
Walied Kamel, Eiji Sugihara, Hiroyuki Nobusue, Sayaka Yamaguchi-Iwai, Nobuyuki Onishi, Kenta Maki, Yumi Fukuchi, Koichi Matsuo, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu
Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro. Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), with AMPK functioning upstream of p38 MAPK...
October 31, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27794047/inhibition-of-akr1c3-activation-overcomes-resistance-to-abiraterone-in-advanced-prostate-cancer
#15
Chengfei Liu, Cameron M Armstrong, Wei Lou, Alan Lombard, Christopher P Evans, Allen C Gao
Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 re-sensitizes resistant cells to abiraterone treatment...
October 28, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27777286/interference-with-the-hsf1-hsp70-bag3-pathway-primes-glioma-cells-to-matrix-detachment-and-bh3-mimetic-induced-apoptosis
#16
Patrick Antonietti, Benedikt Linder, Stephanie Hehlgans, Iris C Mildenberger, Michael C Burger, Simone Fulda, Joachim P Steinbach, Florian Gessler, Franz Rodel, Michel Mittelbronn, Donat Kogel
Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 (heat shock factor 1) acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101-induced cell death and reactivates effector caspase-mediated apoptosis in U251 glioma cells with high BAG3 expression, while these sensitizing effects were less pronounced in U343 cells expressing lower BAG3 levels...
October 24, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27760838/identification-and-validation-of-compounds-selectively-killing-resistant-cancer-delineating-cell-line-specific-effects-from-p-glycoprotein-induced-toxicity
#17
András Füredi, Szilárd Tóth, Kornélia Szebényi, Veronika F S Pape, Dóra Türk, Nóra Kucsma, László Cervenák, József Tóvári, Gergely Szakács
Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study our aim was to catalogue various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp) overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp...
October 19, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27760837/6%C3%AE-acetoxyanopterine-a-novel-structure-class-of-mitotic-inhibitor-disrupting-microtubule-dynamics-in-prostate-cancer-cells
#18
Claire Levrier, Martin C Sadowski, Anja Rockstroh, Brian Gabrielli, Maria Kavallaris, Melanie Lehman, Rohan A Davis, Colleen C Nelson
The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis...
October 19, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27760836/preclinical-efficacy-of-an-antibody-drug-conjugate-targeting-mesothelin-correlates-with-quantitative-89zr-immunopet
#19
Anton G T Terwisscha van Scheltinga, Annie Ogasawara, Glenn Pacheco, Alexander Vanderbilt, Jeff Tinianow, Nidhi Gupta, Dongwei Li, Ron Firestein, Jan Marik, Suzie J Scales, Simon-Peter Williams
Antibody-drug conjugates (ADCs) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr) labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3 X2...
October 19, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27760835/n-arachidonoyl-dopamine-inhibits-nras-neoplastic-transformation-by-suppressing-its-plasma-membrane-translocation
#20
Min Wu, Jinyan Huang, Jianming Zhang, Cyril Benes, Bo Jiao, Ruibao Ren
RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block the RAS oncogenic signaling by a distinct mechanism. Since the biological activity of RAS proteins rely upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors...
October 19, 2016: Molecular Cancer Therapeutics
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