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In many cancers, a high constitutive activation of transcription factor NF-?B has been implicated in tumor progression and apoptosis resistance, making NF-?B an attractive target for cancer therapy. Here, we describe the specific inhibition of NF-?B by the intracellular delivery of I?Ba through VP22-mediated protein transduction. The Herpes virus protein VP22 has attracted great attention in gene therapy, because of its ability to migrate from an original expressing cell into surrounding recipient cells, resulting in high levels of protein transduction. To evaluate the use of VP22 as a vehicle for NF-?B inhibition, we expressed several versions of VP22-I?Ba fusion proteins in baculovirus, bacteria, and mammalian cells. While we could not detect transcellular migration of different VP22-I?Ba constructs, interestingly, baculovirally expressed VP22-I?Ba was efficiently delivered into cells after exogenous administration. The purified and imported VP22-I?Ba retained its function and efficiently inhibited both constitutive and inducible NF-?B activation. We further show that the 34 C-terminal amino acids of VP22 were sufficient for the import property, suggesting also that the ability of intercellular migration and cellular import are not linked to each other. Together, our results demonstrate that recombinant VP22 acts as an efficient vehicle for the exogenous delivery of I?Ba and, moreover, might find applications to block NF-?B activation specifically.Oncogene (2003) 22, 5367-5373. doi:10.1038/sj.onc.1206544 [ABSTRACT FROM AUTHOR]

High-level MET amplification (METamp) is a primary driver in ∼1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median duration of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992)., Competing Interests: Declaration of interests X.L. reported personal/consulting fees from EMD Serono during the conduct of the study; personal or consulting fees from AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Janssen, Blueprint Medicines, Bayer, and Albion; grants from ArriVent, Eli Lilly, Boehringer Ingelheim, and Regeneron; and personal fees from AbbVie outside the submitted work. L.G.P.-A. reported consulting roles with AstraZeneca, Lilly, EMD Serono, Spectrum Pharmaceuticals, and Daiichi Sankyo/Eli Lilly; research funding from Lilly and Boehringer Ingelheim; leadership roles from Genomica and ALTUM Sequencing; speakers bureau from Merck & Co., Kenilworth, NJ, Bristol-Myers Squibb, Roche, Pfizer, Lilly, AstraZeneca, and the healthcare business of Merck KGaA, Darmstadt, Germany; travel/accommodations/expenses from Roche, AstraZeneca, Merck & Co., Kenilworth, NJ, Bristol-Myers Squibb, Pfizer, and Takeda; and honoraria from Roche, Lilly, Pfizer, Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, AstraZeneca, the healthcare business of Merck KGaA, Darmstadt, Germany, PharmaMar, Novartis, Celgene, Amgen, Sanofi, Ipsen, Servier, Bayer, Blueprint Medicines, Mirati Therapeutics, and Takeda outside the submitted work. J.V.M. reported an advisory role with Amgen outside the submitted work. S.V. reported consulting or advisory role from the healthcare business of Merck KGaA, Darmstadt, Germany, AbbVie, Bristol-Myers Squibb, AstraZeneca, Merck & Co., Kenilworth, NJ, and Roche; non-financial support from OSE Immunotherapeutics; and personal fees from Janssen and Puma Biotechnology outside the submitted work. C.C.G. reported a consulting/advisory role with Boehringer Ingelheim and travel/accommodations/expenses from Roche and Merck & Co., Kenilworth, NJ, outside the submitted work. E.F.S. reported an advisory/consultancy role (institution) with Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol-Myers Squibb, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Takeda, Bayer, Regeneron, Novartis, Daiichi Sankyo, and Seattle Genetics; and research funding (institution) from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca, and Bristol-Myers Squibb outside the submitted work. M.G. reported personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study; grants and personal fees from AstraZeneca; and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, Bayer, Bristol-Myers Squibb, AbbVie, Takeda, Janssen, Roche, Sanofi, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, and Blueprint outside the submitted work. R.V. reported research funding from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study; personal consulting fees from Janssen; personal speaker fees from Bristol-Myers Squibb and Takeda; personal speaker bureau fees from Amgen, Sanofi, Roche, and AstraZeneca; and travel fees from Pfizer Travel and Janssen outside the submitted work. D.V.B. reported advisory/consultancy honoraria from Roche, the healthcare business of Merck KGaA, Darmstadt, Germany, Bristol-Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, and Takeda; and speaker honoraria from Roche, the healthcare business of Merck, KGaA, Darmstadt, Germany, Bristol-Myers Squibb, AstraZeneca, Pfizer, and Boehringer Ingelheim outside the submitted work. J.F.P. reported consulting/advisory roles with Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, and GlaxoSmithKline outside the submitted work. M.S. reported an advisory/consulting role with Roche, AstraZeneca, Bristol-Myers Squibb, and Merck & Co., Kenilworth, NJ, outside the submitted work. T.K. reported grants and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, and Kyowa Hakko Kirin; personal fees from Ono Pharmaceutical, Pfizer Japan, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, and Daiichi-Sankyo; and grants from the healthcare business of Merck KGaA, Darmstadt, Germany, outside the submitted work. Y.-C.K. reported honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, Pfizer, Ono, Bristol-Myers Squibb, Daiichi Sankyo, and Yuhan; and research funding from AstraZeneca, Roche, and Boehringer Ingelheim outside the submitted work. S.S.Y. reported honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, and Yuhan; and research funding from AstraZeneca, Roche, and Boehringer Ingelheim outside the submitted work. J.-Y.H. reported research funding from Hoffmann-La Roche, Ltd., Ono Pharmaceutical, Pfizer, and Takeda outside the submitted work. J.-H.K. reported honoraria from Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, and Bristol-Myers Squibb; consulting roles with Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, AstraZeneca, and Yuhan; speakers bureau for Pfizer, Merck & Co., Kenilworth, NJ, and Roche; and research funding from Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, and Yuhan outside the submitted work. Y.J.C. reported consulting/advisory role with Astella, Yuhan, Merck & Co., Kenilworth, NJ, Roche, and Chong Kun Dang outside the submitted work. C.S. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. D.J. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. H.V. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. R.B. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. G.O. was an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, at the time of the study and holds stock in Novartis. A.J. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. P.K.P. reported an advisory/consulting role from Takeda, Xencor, Janssen, CrownBio, Bicara, Mirati, and EMD Serono; and research funding (institution) from Bicara, Boehringer Ingelheim, and EMD Serono outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The mesenchymal-epithelial transition factor (MET) proto-oncogene encodes the MET receptor tyrosine kinase. MET aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms, including MET mutations, gene amplification, rearrangement, and overexpression. Therefore, MET is a therapeutic target and the selective type Ib MET inhibitor, tepotinib, was designed to potently inhibit MET kinase activity. In vitro, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and in vivo, tepotinib exhibits marked, dose-dependent antitumor activity in MET-dependent tumor models of various cancer indications. Tepotinib penetrates the blood-brain barrier and demonstrates strong antitumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. MET amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI), and preclinical studies show that tepotinib in combination with EGFR TKIs can overcome this resistance. Tepotinib is currently approved for the treatment of adult patients with advanced or metastatic non-small cell lung cancer harboring MET exon 14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring MET alterations and demonstrates that strong adherence to the principles of the Pharmacological Audit Trail may result in a successful discovery and development of a precision medicine., (©2023 The Authors; Published by the American Association for Cancer Research.)