Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer
In conclusion, L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells particularly using a low dose of afatinib, and these minor mutations appear to exhibit sensitivity to dacomitinib and erlotinib, respectively. These secondary mutations should be tested in clinical practice. Mol Cancer Ther; 16(2); 357–64. ©2016 AACR.
See related article by Talbert et al., p. 344 (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Kobayashi, Y., Azuma, K., Nagai, H., Kim, Y. H., Togashi, Y., Sesumi, Y., Chiba, M., Shimoji, M., Sato, K., Tomizawa, K., Takemoto, T., Nishio, K., Mitsudomi, T. Tags: Cancer Biology and Signal Transduction Source Type: research
Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and -Intrinsic Activities
Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity 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 anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented mus...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Talbert, E. E., Yang, J., Mace, T. A., Farren, M. R., Farris, A. B., Young, G. S., Elnaggar, O., Che, Z., Timmers, C. D., Rajasekera, P., Maskarinec, J. M., Bloomston, M., Bekaii-Saab, T., Guttridge, D. C., Lesinski, G. B. Tags: Cancer Biology and Signal Transduction Source Type: research
Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation
Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflam...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Quan-Jun, Y., Yan, H., Yong-Long, H., Li-Li, W., Jie, L., Jin-Lu, H., Jin, L., Peng-Guo, C., Run, G., Cheng, G. Tags: Cancer Biology and Signal Transduction Source Type: research
Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model
Hepatocellular carcinoma, a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Here, we examined the therapeutic efficacy of CCL2–CCR2 axis inhibitors against hepatitis and hepatocellular carcinoma in the miR-122 knockout (a.k.a. KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to hepatocellular carcinoma with age. Therapeutic potential of ...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Teng, K.-Y., Han, J., Zhang, X., Hsu, S.-H., He, S., Wani, N. A., Barajas, J. M., Snyder, L. A., Frankel, W. L., Caligiuri, M. A., Jacob, S. T., Yu, J., Ghoshal, K. Tags: Large Molecule Therapeutics Source Type: research
Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response
Neuropathic pain is a limiting factor of platinum-based chemotherapies. We sought to investigate the neuroprotective potential of niclosamide in peripheral neuropathies induced by oxaliplatin. Normal neuron-like and cancer cells were treated in vitro with oxaliplatin associated or not with an inhibitor of STAT3 and NF-B, niclosamide. Cell production of reactive oxygen species and viability were measured by 2',7'-dichlorodihydrofluorescein diacetate and crystal violet. Peripheral neuropathies were induced in mice by oxaliplatin with or without niclosamide. Neurologic functions were assessed by behavioral and electrophysiolo...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Cerles, O., Benoit, E., Chereau, C., Chouzenoux, S., Morin, F., Guillaumot, M.-A., Coriat, R., Kavian, N., Loussier, T., Santulli, P., Marcellin, L., Saidu, N. E. B., Weill, B., Batteux, F., Nicco, C. Tags: Small Molecule Therapeutics Source Type: research
Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers
In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD–NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multip...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Sun, K., Atoyan, R., Borek, M. A., Dellarocca, S., Samson, M. E. S., Ma, A. W., Xu, G.-X., Patterson, T., Tuck, D. P., Viner, J. L., Fattaey, A., Wang, J. Tags: Small Molecule Therapeutics Source Type: research
Strategies to Overcome Bypass Mechanisms Mediating Clinical Resistance to EGFR Tyrosine Kinase Inhibition in Lung Cancer
The vast majority of patients with metastatic lung cancers who initially benefit from EGFR-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the challenge of treating tumors resistant to EGFR inhibitors. Resistance mechanisms include new, second-site mutations within EGFR (e.g., T790M and C797S), upregulation of MET kinase, upregulation of insulin growth factor receptor (IGFR), HER2 amplification, increased expression of AXL, BIM modulation, NF-B activation, histologic switch to small-cell cancer, epithelial-to-mesenchymal transiti...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Husain, H., Scur, M., Murtuza, A., Bui, N., Woodward, B., Kurzrock, R. Tags: Review Source Type: research
Mitogen-Activated Protein Kinases Inhibitors: Potential Therapeutic Agents for Cancer Cachexia
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Baracos, V. E. Tags: Commentary Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer
Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the process...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Machitani, M., Sakurai, F., Wakabayashi, K., Tachibana, M., Fujiwara, T., Mizuguchi, H. Tags: Models and Technologies Source Type: research
Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers
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 germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was assoc...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Arora, A., Parvathaneni, S., Aleskandarany, M. A., Agarwal, D., Ali, R., Abdel-Fatah, T., Green, A. R., Ball, G. R., Rakha, E. A., Ellis, I. O., Sharma, S., Madhusudan, S. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R
Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+ release channel inositol 1,4,5-trisphosphate receptor (IP3R) subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. However, the possible antica...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Kang, S., Hong, J., Lee, J. M., Moon, H. E., Jeon, B., Choi, J., Yoon, N. A., Paek, S. H., Roh, E. J., Lee, C. J., Kang, S. S. Tags: Cancer Biology and Signal Transduction Source Type: research
Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors
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 of breast cancer cell migration was attenuated after cotreatment with glutathione. Penfluridol also downregulated Sp transcription factors Sp1, Sp3, and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated miRNAs (miR27a and miR20a/miR17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4. α6- and β4-integrins as well as α5- and β1-integrins are Sp-regulate...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Hedrick, E., Li, X., Safe, S. Tags: Cancer Biology and Signal Transduction Source Type: research
Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma
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 nucle...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Haak, A. J., Appleton, K. M., Lisabeth, E. M., Misek, S. A., Ji, Y., Wade, S. M., Bell, J. L., Rockwell, C. E., Airik, M., Krook, M. A., Larsen, S. D., Verhaegen, M., Lawlor, E. R., Neubig, R. R. Tags: Cancer Biology and Signal Transduction Source Type: research
Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity
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 MAPK, with AMPK functioning upstream of p...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Kamel, W. A., Sugihara, E., Nobusue, H., Yamaguchi-Iwai, S., Onishi, N., Maki, K., Fukuchi, Y., Matsuo, K., Muto, A., Saya, H., Shimizu, T. Tags: Cancer Biology and Signal Transduction Source Type: research
