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Mutation
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  In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant melanoma cell lines of varying levels of resistance to mitogen-activated protein kinase (MAPK) pathway inhibition, we identified the combination of PLX4720, a targeted inhibitor of mutated BRaf, and lapatinib, an inhibitor of the ErbB family of receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to PLX4720.
  The L858R mutation enhances clinical sensitivity to gefitinib and erlotinib as compared with wild type and reduces the relative sensitivity to lapatinib.
  These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib.
  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.
  This study was aimed to investigate the therapeutic effect of two molecular targeted therapeutic drugs, tyrosine kinase inhibitors gefitinib and lapatinib, on JAK2 V617F positive myeloproliferative disorders (MPD).
 The human leukemia cell line (HEL cell line) carrying JAK2 V617F mutation was treated with gefitinib (0.5, 1, 5, 10, 25 µmol/L) and lapatinib (0.5, 1, 2, 4, 8, 16 µmol/L) respectively.
  The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992).
  Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib.
  Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033.
  Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033.
  Of note, EGFR T790M, a receptor variant found in patients with gefitinib-resistant NSCLC, was also resistant to lapatinib-mediated inhibition of receptor autophosphorylation.
  It was found that TKIs can be grouped into three classes in terms of their response behavior to T798M mutation: class I inhibitors exhibit drug resistance upon the mutation, such as lapatinib, TAK-285 and AEE788; class II inhibitors are insensitive to the mutation, such as erlotinib and gefitinib; and class III inhibitors can be sensitized by the mutation, such as staurosporine.
  A missense mutation, L755P, in the HER2 kinase domain has been involved in lung cancer in humans and exhibits reduced response to lapatinib therapy.
 This study offers a structural explanation for the effect of the L755P mutation on the HER2/lapatinib complex.
  ErbB2-T798I engineered cell models indeed show resistance to lapatinib but remain sensitive to the irreversible EGFR/ErbB2 inhibitor, PD168393, suggestive of potential alternative treatment strategies to overcome resistance.
  Moreover, the sErbB3 N418Q mutant enhanced anticancer effects of lapatinib more effectively than the wild type.
  Clinical response to a lapatinib-based therapy for a Li-Fraumeni syndrome patient with a novel HER2V659E mutation.
  A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib.
 RESULTS: A low 3% allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib.
  Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.
  ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance.
  ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers.
  ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance.
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