Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms involved in cellular radioresistance are mostly unknown and may be related to specific genetic alterations. In order to correlate the most frequent oncogenic alterations detected in tumors and ionizing radiation resistance, we studied the effect of irradiation on murine keratinocytes transformed by different oncogenes. Mouse PAM 212 keratinocytes were transformed by transfection or retroviral mediated infection with the oncogenes v-H-ras, v-myc, adenovirus Ela, neu and a mutant p53 (mp53). Cells were gamma irradiated with a Co-60 source. Cell viability was evaluated by the crystal violet method and thymidine uptake and data adjusted to the linear-quadratic model. Surviving fraction 2Gy (SF2) and DO was calculated. Cell cycle study was assessed by incorporation of bromodeoxyridine (BrdUrd) and flow cytometry. p53 protein was studied by Western-blot and apoptosis in DNA agarose gels. The surviving fraction for the different keratinocytes, PAM 212, 212 neo, 212 Ela, 212 v-H-ras, 212 myc, 212 neu and 212 mp53 was 0.79, 0.78, 0.34, 0.82, 0.68, 0.74, and 0.72, respectively. Ela oncogene induced a great sensitivity to irradiation and v-H-ras a mild radioresistance. In flow cytometry, 212 Ela keratinocytes displayed a pronounced and prolonged arrest in G2/M phase. Apoptosis was observed after irradiation only in the 212 Ela keratinocytes. With these results, we conclude that some oncogene products may modulate radiosensitivity in keratinocytes. Mechanisms involved in radiosensitivity mediated by the Ela oncogene seem to be related to p53 protein level, induction of apoptosis and to an irreversible premitotic arrest in G2/M phase, ineffective for repair of DNA damage.
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PMID:Oncogenes and cellular-sensitivity to radiotherapy - a study on murine keratinocytes transformed by v-h-ras, v-myc, v-Neu, adenovirus e1a and mutant p53. 2155 21

Human Epidermal Growth Factor Receptor 2-positive breast cancer (HER2+ BC) is defined by increased amplification of the ERBB2/neu oncogene and/or overexpression of its associated HER2 transmembrane receptor protein. HER2+ BC represents approximately 15-20% of breast cancer, and it is independently associated with a higher grade, more aggressive phenotype, and worse prognosis. With the advent of trastuzumab, the prognostic landscape for HER2+ BC patients has considerably improved. However, both de novo and acquired resistance to trastuzumab remain a significant obstacle for many patients, requiring novel therapies for further clinical benefit. Over the last two decades, there has been extraordinary progress in the development of HER2+ BC treatment regimens, with extensions into HER2-amplified gastroesophageal junction cancer via the NCI-MATCH precision medicine trial program (NCT02465060). Trastuzumab, pertuzumab, T-DM1, and lapatinib are commonly recommended as a single agent (along with chemotherapy) or in combinations of anti-HER2 agents in neoadjuvant, adjuvant and metastatic settings according to National Comprehensive Cancer Network (NCCN) guidelines. Currently, the combination of trastuzumab, pertuzumab, and taxane chemotherapy are first-line for HER2+/HR- metastatic breast cancer with potential breakthrough therapies such as trastuzumab-deruxtecan (DS-8201a), margetuximab and tucatinib (ONT-380) on the horizon. Furthermore, recent clinical trials have demonstrated the potential utility of hormone receptor status, PAM-50 luminal intrinsic subtype, PD-L1, and TIL as predictive biomarkers for response to HER2+ therapies. We briefly introduce the origin of HER2, the invention of trastuzumab, and the classification of HER2+ BC. Each HER2-targeted therapy is then presented by indication, mechanism of action, and relevant clinical trials with subsequent elaboration and contextualization within clinical settings with an epilogue of potential future biomarkers for clinical use in HER2+ BC. We summarize the most significant and updated research in clinical practice relevant to HER2+ BC management and highlight the clinical status of upcoming anti-HER2 agents as well as immunotherapy drugs in combination with anti-HER2 agents.
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PMID:The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. 3236 85