sw044248 and Lung-Neoplasms

SW044248, identified through a screen for chemicals that are selectively toxic for non-small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently from camptothecin and camptothecin did not show the same selective toxicity as SW044248. Elimination of Top1 by siRNA partially protected cells from SW044248, although removing Top1 was itself eventually toxic. Cells resistant to SW044248 responded to the compound by upregulating CDKN1A and siRNA to CDKN1A sensitized those cells to SW044248. Thus, at least part of the differential sensitivity of NSCLC cells to SW044248 is the ability to upregulate CDKN1A.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; DNA Replication; Dose-Response Relationship, Drug; Humans; Indoles; Inhibitory Concentration 50; Lung Neoplasms; Protein Biosynthesis; Stress, Physiological; Topoisomerase I Inhibitors; Transcription Factors; Transcription, Genetic; Triazines; Tumor Cells, Cultured

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Coatomer Protein; Drug Screening Assays, Antitumor; Female; Genes, ras; Heterografts; Humans; Indoles; Lung Neoplasms; Lysosomes; Mice; Molecular Targeted Therapy; Neoplasm Transplantation; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Phosphorylation; Triazines