abt-199 and Carcinoma--Non-Small-Cell-Lung

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Humans; Lung Neoplasms; Mice, SCID; Mitochondria; Mitochondrial Membranes; Sulfonamides

Ibrutinib is a small molecule drug that targets Bruton's tyrosine kinase in B-cell malignancies and is highly efficient at killing mantle cell lymphoma and chronic lymphocytic leukemia. However, the anti-cancer activity of ibrutinib against solid tumors, such as non-small cell lung cancer (NSCLC), remains low. To improve the cytotoxicity of ibrutinib towards lung cancer, we synthesized a series of ibrutinib derivatives, of which Ibr-7 exhibited superior anti-cancer activity to ibrutinib, especially against epithelial growth factor receptor (EGFR) wild-type NSCLC cell lines. Ibr-7 was observed to dramatically suppress the mammalian target of Rapamycin complex 1 (mTORC1)/S6 signaling pathway, which is only slightly affected by ibrutinib, thus accounting for the superior anti-cancer activity of Ibr-7 towards NSCLC. Ibr-7 was shown to overcome the elevation of Mcl-1 caused by ABT-199 mono-treatment, and thus exhibited a significant synergistic effect when combined with ABT-199. In conclusion, we used a molecular substitution method to generate a novel ibrutinib derivative, termed Ibr-7, which exhibits enhanced anti-cancer activity against NSCLC cells as compared with the parental compound.

Topics: Adenine; Animals; Antineoplastic Agents; Apoptosis; Autoantigens; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Drug Synergism; ErbB Receptors; Female; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice, Nude; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Ribonucleoproteins; Ribosomal Protein S6; Signal Transduction; SS-B Antigen; Sulfonamides; TOR Serine-Threonine Kinases; Up-Regulation; Xenograft Model Antitumor Assays