Comparing antibody and small-molecule therapies for cancer

Imai, Kohzoh; Takaoka, Akinori

doi:10.1038/nrc1913

Cited by 673 publications

(566 citation statements)

References 141 publications

Supporting

Mentioning

548

Contrasting

Unclassified

Order By: Relevance

“…The most clinically relevant EGFR mutation found in 50% of the cases showing acquired resistance to EGFR inhibitors (gefitinib and erlotinib) is the T790M mutation located in exon 20 ( Figure 1) [19]. This mutation, which is located within the ATP-binding site of the kinase domain, causes steric hindrance for access of the inhibitor to the cleft owing to the bulkiness of the methionine sidechain [20]. The use of irreversible inhibitors of the EGFR kinase activity to treat patients harboring this mutation is an attractive therapeutic approach, and has prompted the search for new EGFR inhibitors that specifically target the EGFR T790M mutation.…”

Section: Glossarymentioning

confidence: 99%

EGFR and NF-κB: partners in cancer

Shostak

Chariot

2015

Trends in Molecular Medicine

187

160

View full text Add to dashboard Cite

Section: Glossarymentioning

confidence: 99%

EGFR and NF-κB: partners in cancer

Shostak

Chariot

2015

Trends in Molecular Medicine

187

160

View full text Add to dashboard Cite

“…The epidermal growth factor receptor has thus been identified as an important target in cancer therapy (Baselga and Arteaga, 2005). Several agents, including small-molecule inhibitors of the tyrosine kinase activity of EGFR (EGFR-TKIs) and monoclonal antibodies (mAbs) specific for EGFR, have been designed to block EGFR signalling selectively (Ettinger, 2006;Harari and Huang, 2006;Imai and Takaoka, 2006). Among EGFR-TKIs, gefitinib and erlotinib have been extensively evaluated in non-small cell lung cancer (NSCLC), and sensitivity to these drugs has been associated with the presence of somatic mutations in the EGFR kinase domain or with EGFR amplification (Lynch et al, 2004;Paez et al, 2004;Pao et al, 2004;Cappuzzo et al, 2005;Mitsudomi et al, 2005;Takano et al, 2005).…”

mentioning

confidence: 99%

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

et al. 2008

View full text Add to dashboard Cite

The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.

show abstract

“…In contrast with traditional chemotherapeutic drugs, the current armamentarium of approved and investigational targeted agents offers increased selectivity, potency, and efficacy for a wide variety of human malignancies, and typically with more favorable toxicity profiles (1,2). Their cellular targets include growth factor receptors, effector molecules of canonical signaling pathways, protein tyrosine kinases, cell-cycle regulators, and modulators of apoptosis-all of which are essential for normal cellular function but often become dysregulated as a consequence of oncogenic transformation.…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

View full text Add to dashboard Cite

Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespibinduced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

show abstract

Comparing antibody and small-molecule therapies for cancer

Cited by 673 publications

References 141 publications

EGFR and NF-κB: partners in cancer

EGFR and NF-κB: partners in cancer

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Contact Info

Product

Resources

About