Molecular targeted therapy for anticancer treatment

Min, Hye‐Young; Lee, Ho‐Young

doi:10.1038/s12276-022-00864-3

Cited by 150 publications

(69 citation statements)

References 262 publications

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“…Annotation of predictive mutations is critical for evolution of precision oncology, including therapies targeting the ERBB signaling pathway [48][49][50]. Analyses of the role of ERBB family proteins as predictive biomarkers has focused on EGFR and ERBB2 while there is evidence that individual mutations in ERBB3 and ERBB4 could also have clinical signi cance [26, 51,52].…”

Section: Discussionmentioning

confidence: 99%

Trans-activating mutations of the pseudokinase ERBB3

Elenius

Koivu

Chakroborty³

et al. 2023

Preprint

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Genetic changes in the ERBB family of receptor tyrosine kinases serve as oncogenic driver events and predictive biomarkers for ERBB inhibitor drugs. ERBB3 is a pseudokinase member of the family that, although lacking a fully active kinase domain, is well known for its potent signaling activity as a heterodimeric complex with ERBB2. Previous studies have identified few transforming ERBB3 mutations while the great majority of the hundreds of different somatic ERBB3 variants observed in different cancer types remain of unknown significance. Here, we describe an unbiased functional genetics screen of the transforming potential of thousands of ERBB3 mutations in parallel. The screen based on a previously described iSCREAM (in vitro screen of activating mutations) platform, and addressing ERBB3 pseudokinase signaling in a context of ERBB3/ERBB2 heterodimers, identified 18 hit mutations. Validation experiments in Ba/F3, NIH 3T3, and MCF10A cell backgrounds demonstrated the presence of both previously known and unknown transforming ERBB3 missense mutations functioning either as single variants or in cis as a pairwise combination. Drug sensitivity assays with trastuzumab, pertuzumab and neratinib indicated actionability of the transforming ERBB3 variants.

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Section: Discussionmentioning

confidence: 99%

Trans-activating mutations of the pseudokinase ERBB3

Elenius

Koivu

Chakroborty³

et al. 2023

Preprint

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“…Cancer is one of the most important health problems facing human beings, and how to carry out effective cancer diagnosis and treatment is a major challenge in the current biomedical field. Traditional therapeutic methods, such as surgery, 1 radiotherapy, 2 chemotherapy 3 and targeted therapy, 4 can effectively kill tumor cells, but they also have disadvantages including low targeting, lack of specificity, drug resistance and strong side effects. Therefore, it is urgent to find more effective, safe and reliable means of diagnosing and treating cancer.…”

Section: Introductionmentioning

confidence: 99%

Rational design of amphiphilic BODIPY-based photosensitizers for multimodal imaging-guided phototherapy

Jiang

Zhang

et al. 2023

Mater. Chem. Front.

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“…Lung cancer is one of the most common diseases among humans, with a high mortality rate worldwide. Treatments for this form of cancer focus on inhibiting the formation and growth of tumors by targeting the relevant molecular targets . Several targeted drugs have shown remarkable anticancer activity by explicitly blocking the driver oncogene-oriented signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors

et al. 2023

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The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9−13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC 50 values of ca. 0.6−10.2 nM) compared to the known drug erlotinib (IC 50 of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.

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Molecular targeted therapy for anticancer treatment

Cited by 150 publications

References 262 publications

Trans-activating mutations of the pseudokinase ERBB3

Trans-activating mutations of the pseudokinase ERBB3

Rational design of amphiphilic BODIPY-based photosensitizers for multimodal imaging-guided phototherapy

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors

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