Patients with advanced non–small-cell lung cancer with a PD-L1 expression level of 1% or more of tumor cells were randomly assigned to receive nivolumab plus ipilimumab, nivolumab alone, or ...chemotherapy. Overall survival was significantly longer among the patients who received nivolumab plus ipilimumab than among those who received chemotherapy.
Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent ...inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is ...implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible ...tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.
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HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of breast cancer patients and predicts a ...poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.
Activation of intracellular mitogenic signal transduction pathways driven by the ErbB family of receptor tyrosine kinases has been implicated in a variety of cancers. Amongst these, the tumorigenic ...roles of the Epidermal Growth Factor receptor (EGFR) and HER-2 have been most extensively studied. Therapeutic antibodies and small molecule kinase inhibitors targeting EGFR have recently received regulatory agency approval for the treatment of colon and lung cancer, respectively. In this review, I briefly describe these agents and their potential use in inhibiting the growth of tumors that overexpress HER-2. I also discuss other therapeutics currently available or being developed specifically to target HER-2 dependent tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have ...occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIll) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvlII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvll mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIIi in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI272, dramatically reduced the size of these EGFRvll-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvlII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.
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A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth ...factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.
The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR
kinase provides a therapeutic opportunity in these patients. GSK1838705A ...is a small-molecule kinase inhibitor that inhibits
IGF-IR and the insulin receptor with IC 50 s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma,
and retards the growth of human tumor xenografts in vivo . Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at
efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic
large-cell lymphomas, some neuroblastomas, and a subset of non–small cell lung cancers. GSK1838705A inhibits ALK, with an
IC 50 of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers. Mol
Cancer Ther 2009;8(10):2811–20
Purpose: Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development
of many types of tumors, including prostate, colon, breast, ...pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR
activity may be useful in treatment of patients with various cancers.
Experimental Design: Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound
on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity
was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor
(IR) was measured in vivo , and the effect on glucose metabolism was evaluated.
Results: GSK1904529A selectively inhibits IGF-IR and IR with IC 50 s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to
cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple
myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human
tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity
of GSK1904529A on IR in vitro and in vivo , minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity.
Conclusion: GSK1904529A is a promising candidate for therapeutic use in IGF-IRâdependent tumors.
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