pi103 and Lung-Neoplasms

pi103 has been researched along with Lung-Neoplasms* in 10 studies

Other Studies

10 other study(ies) available for pi103 and Lung-Neoplasms

ArticleYear
Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer.
    Acta pharmacologica Sinica, 2021, Volume: 42, Issue:4

    The third-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), represented by osimertinib, has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer (NSCLC) with EGFR mutation. However, resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood. In this study, we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations. We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells, evidenced by increased levels of γH2AX and higher intensity of the comet tail after withdrawal from cisplatin. Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK, a key kinase in DNA damage response (DDR), sensitized the resistant cells to osimertinib. Combination of osimertinib with the DNA-PK inhibitor, PI-103, or NU7441, synergistically suppressed the proliferation of the resistant cells. Mechanistically, we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest. These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair, and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.

    Topics: Acrylamides; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Chromones; DNA Damage; DNA Repair; DNA-Activated Protein Kinase; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Furans; Humans; Lung Neoplasms; Morpholines; Mutation; Protein Kinase Inhibitors; Pyridines; Pyrimidines

2021
Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors.
    Bioorganic & medicinal chemistry, 2018, 02-01, Volume: 26, Issue:3

    A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.

    Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Enzyme Activation; Half-Life; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Microsomes, Liver; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship; Transplantation, Heterologous

2018
Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors.
    European journal of medicinal chemistry, 2017, Mar-31, Volume: 129

    ATP-competitive mTOR inhibitors have been studied as potential antitumor agents. Based on the structure-activity relationship of known mTOR inhibitors, a series of novel imidazo[1,2-b]pyridazine derivatives were synthesized and characterized. The anti-proliferative activities of these compounds were evaluated by SRB assay against six human cancer cell lines. Imidazo[1,2-b]pyridazine diaryl urea derivatives A15-A24 exhibited significant anti-proliferative activity especially against non-small cell lung cancer A549 and H460 with IC

    Topics: A549 Cells; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Heterografts; Humans; Lung Neoplasms; Mice, Nude; Protein Kinase Inhibitors; Pyridazines; TOR Serine-Threonine Kinases

2017
ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K-RAS activity to PI3K inhibition.
    Cancer biology & therapy, 2014, Mar-01, Volume: 15, Issue:3

    K-RAS mutated (K-RASmut) non-small cell lung cancer (NSCLC) cells are resistant to EGFR targeting strategies. We investigated the impact of K-RAS activity irrespective of mutational status in the EGFR-independent increase in clonogenic cell survival. An analysis of the K-RAS activity status revealed a constitutively high K-RAS activity in K-RASmut NSCLC cells and also in head and neck squamous cell carcinoma (HNSCC) cells overexpressing wild-type K-RAS (K-RASwt). Similar to K-RAS-mutated cells, increased K-RAS activity in HNSCC cells overexpressing K-RASwt was associated with the stimulated production of the EGFR ligand amphiregulin and resistance to EGFR tyrosine kinase (EGFR-TK) inhibitors such as erlotinib. Expression of mutated K-RAS stimulated Akt phosphorylation and increased plating efficiency. Conversely, knockdown of K-RAS in K-RASmut NSCLC cells and in HNSCC cells presenting overexpression of K-RASwt resulted in sensitization to the anti-clonogenic activity of erlotinib. K-RAS activity results in EGFR-dependent and EGFR-independent Akt activity. The short-term treatment (2 h) of cells with EGFR-TK or PI3K inhibitors (erlotinib and PI-103) resulted in the repression of Akt activation, whereas long-term treatment (24 h) with inhibitors led to the reactivation of Akt and improved clonogenicity. The Akt re-activation was MAPK-ERK2-dependent and associated with a lack of complete response to anti-clonogenic activity of PI-103. A complete response was observed when PI-103 was combined with MEK inhibitor PD98059. Together, clonogenicity inhibition in tumor cells presenting constitutive K-RAS activity independent of K-RAS mutational status can be achieved by targeting of EGFR downstream pathways, i.e., PI3K alone or the combination of PI3K and MAPK inhibitors.

    Topics: Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Clone Cells; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Flavonoids; Furans; Head and Neck Neoplasms; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Quinazolines; ras Proteins; Signal Transduction

2014
Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K/mTOR inhibitor PI103 by lysosome-mediated apoptosis.
    Anti-cancer drugs, 2013, Volume: 24, Issue:1

    On the basis of previous findings that certain lung carcinoma cell lines are resistant to the dual PI3K/mTOR inhibitor PI103, we searched for new strategies to overcome this resistance. Here, we report that the lysosomotropic agent chloroquine (CQ) reverses the resistance of lung carcinoma cells to PI3K/mTOR inhibition and primes cells for PI103-induced apoptosis. Investigations of the underlying mechanism of this cooperative interaction show that PI103 increases lysosomal volume and function, as indicated by upregulation of the lysosomal marker protein LAMP-1 and maturation of the lysosomal enzyme cathepsin B, whereas CQ destabilizes lysosomal membranes. Together, CQ and PI103 act in concert to trigger lysosomal membrane permeabilization, resulting in the activation of caspases and apoptosis. The broad-range caspase inhibitor zVAD.fmk significantly decreases PI103-induced and CQ-induced loss of cell viability, indicating that caspases are required for cell death induction. Importantly, inhibition of lysosomal enzymes by CA-074me significantly reduces PI103-mediated and CQ-mediated loss of cell viability, showing that lysosomal enzymes are critical mediators of PI103/CQ-induced cytotoxicity. In conclusion, CQ overcomes resistance of lung carcinoma cells to PI103-induced apoptosis by cooperating with PI103 to trigger lysosome-mediated apoptosis. These findings have important implications for developing effective PI3K/mTOR inhibitor-based therapies for lung cancer.

    Topics: Antineoplastic Agents; Apoptosis; Cathepsin B; Cell Line, Tumor; Cell Survival; Chloroquine; Drug Resistance, Neoplasm; Furans; Humans; Intracellular Membranes; Lung Neoplasms; Lysosomal-Associated Membrane Protein 1; Lysosomes; Permeability; Phosphoinositide-3 Kinase Inhibitors; Pyridines; Pyrimidines; TOR Serine-Threonine Kinases; Up-Regulation

2013
Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2011, Apr-15, Volume: 17, Issue:8

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET that restores downstream mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells PC-9 and HCC827.. We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo.. Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model by using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments by considering short half-life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF.. These results indicate that transient blockade of PI3K/Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in EGFR mutant lung cancer.

    Topics: Animals; Apoptosis; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Furans; Gefitinib; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Mice; Mice, SCID; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Signal Transduction; Xenograft Model Antitumor Assays

2011
Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.
    Cancer research, 2010, Feb-01, Volume: 70, Issue:3

    Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFR(T790M) resistance mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFR(T790M) gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR.

    Topics: Afatinib; Amino Acid Substitution; Animals; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Line, Tumor; Cell Proliferation; Cluster Analysis; Drug Resistance, Neoplasm; ErbB Receptors; Furans; Humans; Lung Neoplasms; Molecular Structure; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Receptor, ErbB-2; Signal Transduction

2010
Inducible EGFR T790M-mediated gefitinib resistance in non-small cell lung cancer cells does not modulate sensitivity to PI103 provoked autophagy.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2010, Volume: 5, Issue:6

    Non-small cell lung cancer (NSCLC) with certain activating mutations in the epidermal growth factor receptor (EGFR) is sensitive to the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib, although acquired resistance eventually develops. Resistance is often mediated by acquisition of the T790M mutation in the activated EGFR allele. The aim of this study was to investigate in an EGFR tyrosine kinase inhibitor sensitive NSCLC cell line model, the impact of induced EGFR T790M expression on the cell biology and sensitivity to novel therapeutic strategies.. Doxycycline inducible EGFR T790M-mediated drug resistance was generated in the clinically relevant HCC827 NSCLC cell line. Cell fate, the activities of EGFR and downstream signaling molecules, and the sensitivity to downstream inhibition of EGFR signaling networks were examined in the presence or absence of induced EGFR T790M expression.. Inducible EGFR T790M expression generated acquired resistance to EGFR inhibitors in HCC827 cells as expected. However, induced EGFR T790M expression did not affect activity of EGFR downstream signaling pathways or cell proliferation under the conditions tested. Moreover, sensitivity to inhibition of signaling molecules downstream of EGFR was unaffected by induced EGFR T790M. Importantly, HCC827 cells remained sensitive to class I phosphatidyl-inositol-3-kinase and mammalian target of rapamycin inhibition, which provoked pronounced autophagy, without significant apoptosis.. Phosphatidyl-inositol-3-kinase /mammalian target of rapamycin inhibition is a potentially effective therapeutic strategy against NSCLC with acquired resistance to EGFR inhibition. However, the implications of drug-induced autophagy in NSCLC need further exploration.

    Topics: Antineoplastic Agents; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Furans; Gefitinib; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Mutation; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases; Pyridines; Pyrimidines; Quinazolines; TOR Serine-Threonine Kinases

2010
Relationship of deregulated signaling converging onto mTOR with prognosis and classification of lung adenocarcinoma shown by two independent in silico analyses.
    Cancer research, 2009, May-01, Volume: 69, Issue:9

    There is marked disparity with a slight overlap among prognosis-predictive signatures reported thus far for lung cancers. In this study, we aimed at linking poor prognosis with particular pathways and/or functions of the gene sets involved to better understand the underlying molecular characteristics associated with the prognosis of lung adenocarcinomas. Gene set enrichment analysis identified a gene set down-regulated by rapamycin as the most significant, whereas several others responsive to withdrawal of glucose or amino acids, which are related to signaling converging onto mammalian target of rapamycin (mTOR), were also shown to be significantly associated, in addition to those related to DNA damage response and cell cycle progression. We also used connectivity map (C-MAP) analysis, an independent bioinformatics approach, to search for Food and Drug Administration-approved drugs that potentially transform an unfavorable signature to a favorable one. Those results identified inhibitors of phosphatidylinositol 3-kinase (PI3K) and mTOR, as well as unexpected drugs such as phenothiazine antipsychotics and resveratrol as potential candidates. Experimental validation revealed that the latter unexpected agents also inhibited signaling converging onto mTOR and exhibited antitumor activities. In addition, deregulation of multiple signaling converging onto mTOR was shown to be significantly associated with sensitivity to PI-103, a dual specificity PI3K/mTOR inhibitor that is not contained in the C-MAP database, lending further support for the connection. Our results clearly show the existence of gene set-definable, intrinsic heterogeneities in lung adenocarcinomas, which seem to be related to both clinical behavior and sensitivity to agents affecting the identified pathways.

    Topics: Adenocarcinoma; Cell Line, Tumor; Computational Biology; Furans; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Oligonucleotide Array Sequence Analysis; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

2009
A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells.
    International journal of molecular medicine, 2009, Volume: 24, Issue:1

    PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin (mTOR) shows high antitumor activity in glioma xenografts. In the present study, clear antitumor activity was observed with PI-103 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460, by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition. In addition, H460 cells with activating mutations of PIK3CA were more sensitive to PI-103 than A549 cells with wild-type PIK3CA. PI-103 was found to inhibit growth by causing G0-G1 arrest in A549 and H460 cells. Western blotting showed that PI-103 induced down-regulation of cyclin D1 and E1 and simultaneously up-regulated p21 and p27, associated with arrest in the G0-G1 phase of the cell cycle. Furthermore, p53, the tumor suppressor which transcriptionally regulates p21, was also upregulated with PI-103 treatment. Collectively, our results suggest that multitargeted intervention is the most effective tumor therapy, and the cooperative blockade of PI3Kalpha and mTOR with PI-103 shows promise for treating gefitinib-resistant NSCLC.

    Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Furans; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrimidines; Quinazolines; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

2009