The serine/threonine kinase Akt lies at a critical signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with molecular targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or molecular targeted agents. Mol Cancer Ther; 9(7); 1956-67.
Fibroblast growth factor receptor (FGFR) signaling is deregulated in many human cancers and FGFR is considered a valid target in FGFR-deregulated tumors. Here we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1Hpyrazolo[3,4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with half-maximal inhibitory concentration (IC 50) values of 1.4-3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC 50 , 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase 1-3 trials ongoing. Research.
Background: FGFs (fibroblast growth factors) and their receptors (FGFRs) play crucial roles in regulation of cell proliferation, survival, migration and differentiation. The FGFRs are comprised of four subtypes (FGFR1∼4) and their gene abnormalities such as gene amplification, translocation and mutations have been reported in multiple cancers including breast, bladder, lung, gastric, endometrial and multiple myeloma. We have identified a highly potent and selective irreversible FGFR inhibitor, TAS-1201) which inhibits all 4 subtypes of FGFR. In this report, we present the in vitro efficacy of this compound in tumor cells harboring the various FGFR gene abnormalities. In addition, we present the antitumor efficacy and pharmacodynamic (PD) activity of in vivo xenograft models. Materials and Methods: For a growth inhibition assay, various tumor cells with FGFR gene abnormalities were treated with TAS-120 for 3 days, and living cells were determined by using CellTiter-Glo™ which measures cellular ATP. Cellular phosphorylation of FGFR and its inhibition by TAS-120 were assayed using ELISA (R&D Systems) or western blotting method. For analysis of in vivo antitumor efficacy, various tumor cell lines were subcutaneously implanted into the side flank of nude mice. Dosing of compound was started when transplanted tumor size reached > ∼ 200 mm3 and tumor size was measured with digital calipers for the entire treatment period. To confirm target engagement by TAS-120 in human tumor xenograft models, we determined FGFR phosphorylation in tumor as a pharmacodynamic marker. FGFR phoshorylation in tumor was determined by ELISA or western blotting. Results: In a cell proliferation assay, TAS-120 selectively inhibited growth of human cancer cell lines with FGFR gene abnormalities. Growth of cell lines without FGFR abnormalities were not inhibited by TAS-120 treatment. TAS-120 inhibited cellular phosphorylation of FGFR as well as intercellular signaling pathways downstream of FGFR in these cells. In addition, TAS-120 inhibited tumor growth in human tumor xenograft mouse models and FGFR phosphorylation in tumor in a dose-dependent manner. Conclusion: TAS-120 is a highly potent irreversible FGFR inhibitor. It selectively inhibited growth of human cancer cell lines selectively, in a FGFR gene abnormality-dependent manner. In addition, TAS-120 demonstrated tumor growth inhibition in mice xenograft models. PD assays suggested this compound inhibits FGFR activity in human tumor xenograft models. 1) 24th EORTC-NCI-AACR Symposium (2012) abstract #380 & #383 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A270. Citation Format: Hiroaki Ochiiwa, Hidenori Fujita, Kimihiro Itoh, Hiroshi Sootome, Akihiro Hashimoto, Yayoi Fujioka, Yoko Nakatsuru, Nobuyuki Oda, Kazuhiko Yonekura, Hiroshi Hirai, Teruhiro Utsugi. TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A270.
Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1−4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I−III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.
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