Current and future targeted therapies for non-small-cell lung cancers with aberrant EGF receptors

Kanthala, Shanthi; Pallerla, Sandeep; Jois, Seetharama D.

doi:10.2217/fon.14.312

Cited by 14 publications

(13 citation statements)

References 110 publications

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“… 25 , 49 , 51 , 52 Preclinical modeling and analysis of tumor tissues obtained from patients after disease progression has also identified other less frequent mechanisms of acquired resistance, including bypass or alternative pathways ( HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, NF1 loss, and potentially FGFR signaling), histological/phenotypic transformation (small-cell lung cancer transformation or epithelial-to-mesenchymal transition), and unknown in 20%–30%. 4 , 17 , 25 , 41 , 53 – 55 Understanding the biological basis responsible for the acquired resistance has therapeutic implications, and several strategies are currently under investigation. Based on the aforementioned mechanisms, several combinations with other therapies targeting bypass or alternative activating pathways have been explored in preclinical models or clinical trials.…”

Section: First-generation Egfr/her-tkismentioning

confidence: 99%

“…Possible mechanisms of acquired resistance have been described, including tertiary EGFR mutations (C797S, L844V, and L718Q), alternative/bypass signaling (increased RAS/RAF/ERK signaling by NRAS E63K0 mutation, BRAF V600E mutation or increased MEK1 activity, HER2 amplification, MET amplification, and PIK3CA E545K mutation), and phenotypic alterations (epithelial–mesenchymal transition and small-cell lung cancer transformation). 4 , 47 Due to the diversity of resistance mechanisms, various therapeutic regimens are under investigation in preclinical and clinical settings. The medical model of combination therapy may be the main trend to enhance their effectiveness.…”

Section: Third-generation Egfr/her-tkismentioning

confidence: 99%

“…2 Non-small-cell lung cancer (NSCLC), accounting for a high proportion (85%–90%) in lung cancer, 3 is subdivided histologically into adenocarcinoma, squamous-cell carcinoma, large-cell carcinoma, and other types. 4 , 5 In the last decade, the diagnosis and treatment of NSCLC has evolved dramatically from the traditional “one-size-fits-all” chemotherapeutic approach to new anticancer compounds molecularly targeting oncogenic driver mutations, due to the advances in cancer biology and technology. Various driver genomic alterations have been identified in oncogene-dependent NSCLC, especially two genes: the human epidermal growth factor receptor ( EGFR/HER ) and the anaplastic lymphoma kinase ( ALK ).…”

Section: Introductionmentioning

confidence: 99%

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Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring <em>EGFR</em> mutations: a review of the evidence

Wang¹,

Goldstein²,

Crowe³

et al. 2016

OTT

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Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFRL858R and EGFRDel19, in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFRT790M mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFRT790M, and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFRT790M resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFRT790M and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFRT790M resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second- and third-generation EGFR/HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.

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Section: First-generation Egfr/her-tkismentioning

confidence: 99%

Section: Third-generation Egfr/her-tkismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring <em>EGFR</em> mutations: a review of the evidence

Wang¹,

Goldstein²,

Crowe³

et al. 2016

OTT

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“…Our aim was to design peptidomimetic dimerization inhibitors that would inhibit the heterodimerization of EGFR by hindering their protein-protein interaction sites. We designed a novel symmetric cyclic peptidomimetic compound 18 (Figure 1 ) [ 22 ] that inhibits HER2:HER3 and EGFR:HER2 heterodimerization. With the L-Pro-D-Pro sequence in the cyclic structure, compound 18 exhibits a β-turn/β-hairpin structure in solution.…”

Section: Introductionmentioning

confidence: 99%

A peptidomimetic with a chiral switch is an inhibitor of epidermal growth factor receptor heterodimerization

et al. 2017

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Among different types of EGFR dimers, EGFR-HER2 and HER2-HER3 are well known in different types of cancers. Targeting dimerization of EGFR will have a significant impact on cancer therapies. A symmetric peptidomimetic was designed to inhibit the protein-protein interaction of EGFR. The peptidomimetic (Cyclo(1,10)PpR (R) Anapa-FDDF-(R)-Anapa)R, compound 18) was shown to exhibit antiproliferative activity with an IC50 of 194 nM in HER2-expressing breast cancer cell lines and 18 nM in lung cancer cell lines. The peptidomimetic has a Pro-Pro sequence in the structure to stabilize the β-turn and a β-amino acid, amino napthyl propionic acid. To investigate the effect of the chirality of β-amino acid on the structure of the peptide and its antiproliferative activity, diastereoisomers of compound 18 were designed and synthesized. Structure-activity relationships of these compounds indicated that there is a chiral switch at β-amino acid in the designed compound. The peptidomimetic with R configuration at β-amino acid and with a L-Pro-D-Pro sequence was the most active compound (18). Using enzyme complement fragmentation assay and proximity ligation assay, we show that compound 18 inhibits HER2:HER3 and EGFR:HER2 dimerization. Surface plasmon resonance studies suggested that compound 18 binds to the HER2 extracellular domain and in particular to domain IV. The anticancer activity of compound 18 was evaluated using a xenograft model of breast cancer in mice; compound 18 suppressed the tumor growth in mice compared to control. Compound 18 was also shown to have a synergistic effect with erlotinib on EGFR mutated lung cancer cell lines.

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“…On the other hand, clinical trials for osimertinib ( Table 1) have focused on patients with common EGFR mutations (exon 19 deletions and L858R), meanwhile, patients with non-common EGFR mutations, continue to be underrepresented, and targeted therapeutic options for them are limited to first-line afatinib (13). It would then be highly relevant to include these patient subgroups in future clinical trials.…”

mentioning

confidence: 99%

Extending the curve: survival of EGFR-mutated lung cancer patients in the 21st century

Barrón

Zatarain-Barrón

Cardona³

et al. 2018

J. Thorac. Dis.

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Current and future targeted therapies for non-small-cell lung cancers with aberrant EGF receptors

Cited by 14 publications

References 110 publications

Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring <em>EGFR</em> mutations: a review of the evidence

Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring <em>EGFR</em> mutations: a review of the evidence

A peptidomimetic with a chiral switch is an inhibitor of epidermal growth factor receptor heterodimerization

Extending the curve: survival of EGFR-mutated lung cancer patients in the 21st century

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