Irreversible Multitargeted ErbB Family Inhibitors for Therapy of Lung and Breast Cancer

Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).

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“…S4B; ref. 20). ACME analysis associates neuroblastoma cell lines with sensitivity to Aurora kinase (AURK) inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset

et al. 2015

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“…First generation-TKIs (1G-TKIs) refer to reversible TKIs such as gefitinib, erlotinib and icotinib, while afatinib, dacomtinib and neratinib are categorized as irreversible 2G-TKIs (73,74). 3G-TKIs, including AZD-9291 (Osimertinib) and CO-1686 (75), are highly specific irreversible inhibitors for mutated receptors only, which are primarily used to target the secondary resistant mutation T790M (75,76).…”

Section: Discussionmentioning

confidence: 99%

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Yang

Liang

et al. 2017

Oncology Reports

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Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non-small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors (TKIs). While the pathogenic and pharmacological characteristics of common mutations in EGFR have been thoroughly investigated, those of uncommon mutations remain to be elucidated. Traditional approaches to study common mutations by randomized controlled trials are not feasible for uncommon mutations owing to their rarity. Therefore, by systematically reviewing laboratory and clinical studies of the G719X mutation, one of the uncommon mutations, we concluded that the G719X mutation was intermediately sensitive to TKIs, with an average response rate of 35.1% (47/134). Moreover, accordingly, we proposed a comprehensive model to investigate uncommon mutations in EGFR. The model involves both basic and clinical components, composed of structural analyses, functional alterations, cell viabilities and animal models with various types of clinical studies. In this review, we systematically reviewed studies of the G719X mutation and put forward a research model that could be generalized to explore uncommon mutations in diseases associated with gene mutations.

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“…EGFR inhibitors have been widely tested in various malignancies such as breast, lung, pancreatic and head and neck cancers (Mendelsohn & Baselga 2006, Subramaniam et al 2015. EGFR is overexpressed in up to 70% of basal-like TNBC (Livasy et al 2006), but EGFR monotherapies such as gefitinib and erlotinib have to date not been successful for breast cancer (Masuda et al 2012), potentially owing to modulation and crosstalk with other growth factors including IGF1R (i.e.…”

Section: Igf1r and Egfrmentioning

confidence: 99%

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Ochnik

Baxter

2016

Endocrine-Related Cancer

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Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers. 23:11 Review A M Ochnik and R C BaxterDual IGF-directed breast cancer therapies

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Irreversible Multitargeted ErbB Family Inhibitors for Therapy of Lung and Breast Cancer

Cited by 35 publications

References 0 publications

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

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