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TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations.

ABSTRACT: Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced non-small cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of ?1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common EGFR mutations (exon 19 deletions and L858R) and the most potent against cells harboring EGFR-T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common EGFR-G719X, L861Q, and S768I mutations. For recalcitrant EGFR exon 20 insertion mutations, selectivity indexes (wild-type EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors. IMPLICATIONS: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant EGFR mutations.

SUBMITTER: Udagawa H

PROVIDER: S-EPMC6872223 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations.

Udagawa Hibiki H Hasako Shinichi S Ohashi Akihiro A Fujioka Rumi R Hakozaki Yumi Y Shibuya Mikiko M Abe Naomi N Komori Toshiharu T Haruma Tomonori T Terasaka Miki M Fujita Ryoto R Hashimoto Akihiro A Funabashi Kaoru K Yasuda Hiroyuki H Miyadera Kazutaka K Goto Koichi K Costa Daniel B DB Kobayashi Susumu S SS

Molecular cancer research : MCR 20190829 11

Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced non-small cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of ≥1%. Lung cancer and genetically engin ...[more]

PMID: 31467113

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Project description:Some species in the polyphyletic fungal genus Acremonium are important opportunist pathogens. Determining the actual spectrum of species and their incidence in the clinical setting, however, has long been hampered because of the difficulties encountered in phenotypic species-level identification. The goal of this study was to re-identify a large number of clinical isolates morphologically and to confirm the identifications by comparing sequences of the internal transcribed spacer region of the rRNA gene of these isolates to those of type or reference strains of well-known Acremonium species. Of the 119 isolates referred to a United States reference laboratory under the name Acremonium, only 75 were identified morphologically as belonging to that genus. The remainder (44 isolates) were identified as belonging to other morphologically similar genera. The Acremonium clinical isolates were related to species of Hypocreales, Sordariales, and of an incertae sedis family of ascomycetes, Plectosphaerellaceae. A total of 50 of the 75 Acremonium isolates (67%) could be identified by molecular means, the prevalent species being Acremonium kiliense (15 isolates), A. sclerotigenum-A. egyptiacum (11 isolates), A. implicatum (7 isolates), A. persicinum (7 isolates), and A. atrogriseum (4 isolates). One of the most interesting findings of our study was that we identified several species among this large collection of clinical isolates that had not previously been reported from human infections, and we failed to confirm other Acremonium species, such as A. potronii, A. recifei, and A. strictum, that had been considered significant. The most common anatomic sites for Acremonium isolates were the respiratory tract (41.3%), nails (10.7%), and the eye (9.3%). Antifungal susceptibility testing demonstrated high MICs for all agents tested, except for terbinafine. Since numerous isolates could not be identified, we concluded that the list of opportunistic Acremonium species is far from be complete and that a considerable number of additional species will be discovered.

Project description:Study designProspective cohort study.ObjectiveApply a machine learning clustering algorithm to baseline imaging data to identify clinically relevant cervical spondylotic myelopathy (CSM) patient phenotypes.Summary of background dataA major shortcoming in improving care for CSM patients is the lack of robust quantitative imaging tools to guide surgical decision-making. Advanced diffusion-weighted magnetic resonance imaging (MRI) techniques, such as diffusion basis spectrum imaging (DBSI), may help address this limitation by providing detailed evaluations of white matter injury in CSM.MethodsFifty CSM patients underwent comprehensive clinical assessments and diffusion-weighted MRI, followed by DBSI modeling. DBSI metrics included fractional anisotropy, axial and radial diffusivity, fiber fraction, extra-axonal fraction, restricted fraction, and nonrestricted fraction. Neurofunctional status was assessed by the modified Japanese Orthopedic Association, myelopathic disability index, and disabilities of the arm, shoulder, and hand. Quality-of-life was measured by the 36-Item Short Form Survey physical component summary and mental component summary. The neck disability index was used to measure self-reported neck pain. K-means clustering was applied to baseline DBSI measures to identify 3 clinically relevant CSM disease phenotypes. Baseline demographic, clinical, radiographic, and patient-reported outcome measures were compared among clusters using one-way analysis of variance (ANOVA).ResultsTwenty-three (55%) mild, 9 (21%) moderate, and 10 (24%) severe myelopathy patients were enrolled. Eight patients were excluded due to MRI data of insufficient quality. Of the remaining 42 patients, 3 groups were generated by k-means clustering. When compared with clusters 1 and 2, cluster 3 performed significantly worse on the modified Japanese Orthopedic Association and all patient-reported outcome measures (P<0.001), except the 36-Item Short Form Survey mental component summary (P>0.05). Cluster 3 also possessed the highest proportion of non-Caucasian patients (43%, P=0.04), the worst hand dynamometer measurements (P<0.05), and significantly higher intra-axonal axial diffusivity and extra-axonal fraction values (P<0.001).ConclusionsUsing baseline imaging data, we delineated a clinically meaningful CSM disease phenotype, characterized by worse neurofunctional status, quality-of-life, and pain, and more severe imaging markers of vasogenic edema.Level of evidenceII.

Dataset Information

TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations.

Publications

TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant <i>EGFR</i> Mutations.

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