Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma

Wang, Yuli; Guo, Zhitao; Yang, Li; Zhou, Qinghua

doi:10.1515/med-2016-0014

Cited by 13 publications

(5 citation statements)

References 72 publications

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“…Both drugs exhibited high inhibitory activity against wild-type and mutant EGFR. However, they ultimately develop resistance due to secondary mutations (Wang et al, 2016).…”

Section: Summary and Future Prospectsmentioning

confidence: 99%

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Duggirala

Lee

2022

Biomol Ther (Seoul)

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Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wildtype EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second-and thirdgeneration EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/ T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

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“…Both drugs exhibited high inhibitory activity against wild-type and mutant EGFR. However, they ultimately develop resistance due to secondary mutations (Wang et al, 2016).…”

Section: Summary and Future Prospectsmentioning

confidence: 99%

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Duggirala

Lee

2022

Biomol Ther (Seoul)

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“…Use of first generation kinase inhibitors such as erlotinib and gefitinib lead to development of drug resistance and in nearly 50% of NSCLC cases the resistance to TKI therapy is due to the presence of T790M mutation [ 36 ]. We wanted to evaluate whether compound 18 has any effect on the T790M mutation and has any synergistic effect with erlotinib on different cancer cell lines including NCI-H1975 cell lines.…”

Section: Resultsmentioning

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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“…To overcome T790M-mediated resistance, third-generation EGFR TKIs (osimertinib, olmutinib and rociletinib) have been developed. These agents target T790M, re-sensitizing cancer cells to EGFR TKI inhibition [ 93 , 96 , 97 , 98 ]. A recent report of AURA-3 in a randomized phase III clinical trial revealed that osimertinib represents the standard therapy in NSCLC with EGFR -activating mutation after the failure of first-line EGFR-TKIs compared to platinum-based chemotherapy [ 99 ].…”

Section: Egfr Targeted Cancer Therapy Resistance and Overcoming Rementioning

confidence: 99%

Receptor Tyrosine Kinase-Targeted Cancer Therapy

Yamaoka

Kusumoto

Andō

et al. 2018

IJMS

233

154

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In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms.

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Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma

Cited by 13 publications

References 72 publications

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

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

Receptor Tyrosine Kinase-Targeted Cancer Therapy

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