ABSTRACT
Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5-6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment.
ABSTRACT
Introduction: Drug screening assays employing two-dimensional (2D) cultures of cancer cells have been largely replaced by three-dimensional (3D) multicellular tumor spheroid (MCTS) models which more closely represent patient's tumors. The predictive power of the different MCTSs depends on source of the cells, techniques of preparation, and characteristics of the aggregates. Areas covered: The preparation of MCTSs and a comparison of the spheroids assembled from permanent cancer and patient-derived cell lines in respect to the correlation of their chemosensitivity to clinical responses are discussed. Spheroids formed in in vivo in pleural effusion and blood of cancer patients are presented as interesting sources for drug screening. Expert opinion: 3D tumor models for drug screening were adopted to increase the predictive power of assays for success in clinical trials. Cell lines which form dense spheroids differ in physical properties, gene expression, and chemosensitivity from 2D cultures. Still, most of these MCTS models lack characteristics of complex tumor tissues and have not been validated for their adequacy to select clinically useful drugs. Patient-derived spheroids from pleural effusion or blood, namely tumorospheres of circulating tumor cells, are MCTS models most similar to patient's tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Spheroids, Cellular/drug effects , Cell Culture Techniques , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , Humans , In Vitro Techniques , Neoplasms/pathologyABSTRACT
Chemotherapeutic interventions in cancer patients are limited by the appearance of chemoresistance. For instance, advanced lung and ovarian cancer patients relapse invariably after few cycles of platinum-based chemotherapy. Disseminated tumors are characterized by genetic instability/heterogeneity, thus containing or generating a repertoire of resistant subpopulations. At the cellular level, altered drug uptake, efflux, and metabolization, as well as modifications of drug targets, increased repair, and decreased cell death complement the limited perfusion and adverse hypoxic/acidic extracellular conditions at the tumor level in retaining cancer cell viability. Similarly, targeted therapy is rendered ineffective by mutations of the specific target protein within a few months or years of administration. Assessment of the expression profiles of resistant tumor cells revealed extensive changes in numerous pathways affecting hundreds of genes. Therefore, reversal of drug resistance will require individual profiles of drug resistance mediators and the combination of several specific drugs, targeting critical components to provide new therapeutic options.
Subject(s)
Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/therapy , Drug Resistance, Neoplasm , Hepatectomy , Liver Neoplasms/therapy , Liver Transplantation , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/pathology , Combined Modality Therapy , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/etiology , Liver Neoplasms/pathology , MicroRNAs/analysis , MicroRNAs/genetics , Molecular Targeted Therapy , Neoplasm Staging , Niacinamide/therapeutic use , Prognosis , SorafenibABSTRACT
INTRODUCTION: Picoplatin was developed as platinum coordination complex to overcome development of resistance, through conjugation to thioles, by the introduction of a methyl-pyridine moiety into the cisplatin parent structure. Pharmacokinetic parameters of the drug, after intravenous and oral application, were studied in solid tumors and clinical Phase I - III trials performed, in particular in NSCLC and small cell lung cancer (SCLC). Results showed low clinical activity of picoplatin. AREAS COVERED: This article presents an overview of the pharmacokinetic assessments of picoplatin in lung cancer. Specifically, the authors address the relationship between disposition and clinical activity of the drug. EXPERT OPINION: Picoplatin failed to overcome resistance to platinum compounds in lung cancer to achieve significant improved survival of most patients. Even highest doses of the drug reaching 150 m/m² given intravenously every 3 weeks were not sufficient to achieve better response than existing chemotherapeutics and the oral bioavailability of a dose of 200 - 400 mg corresponded only to 80 mg/m² iv. Picoplatin therefore seem to be quite ineffective. Picoplatin is expected to overcome tumor resistance in cases which overexpress thiol-conjugating pathways; however, this was not proved in clinical trials. To conclude, this blocked platinum complex is not able to reverse cisplatin resistance to a significant extent in vivo and its mechanisms and kinetics and of DNA damage failed to produce significant clinical results compared to second-line standard therapy for lung cancer.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Organoplatinum Compounds/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Cell Line, Tumor , Cisplatin/administration & dosage , Cisplatin/pharmacokinetics , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm/drug effects , Humans , Organoplatinum Compounds/administration & dosage , Platinum Compounds/pharmacokinetics , Randomized Controlled Trials as TopicABSTRACT
INTRODUCTION: Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. METHODS: Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. RESULTS: With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. CONCLUSION: The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.