Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent
The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in conjunction with etoposide/carboplatin. The predominant aftereffect of adding another agent to etoposide/carboplatin was additivity. Under additive effects happened frequently in SCLC lines responsive to etoposide/carboplatin. In SCLC lines with little if any reaction to etoposide/carboplatin, more than additive SCLC killing happened within the entire spectrum of SCLC lines but never happened in most SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) concurrently with etoposide/carboplatin resulted mainly in under additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines however, synchronised exposure from the SCLC lines to those agents together with etoposide/carboplatin, generally, led to under additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure from the SCLC lines towards the MDM2 inhibitor JNJ-27291199 created enhanced killing in 80% from the SCLC lines. Chk-1 inhibitors for example rabusertib elevated the cytotoxicity of etoposide/carboplatin towards the SCLC lines within an additive to more than additive manner. The mixture of GSK-3ß inhibitor LY-2090314 with etoposide/carboplatin elevated killing in roughly 40% from the SCLC lines. Contact with the BET bromodomain inhibitor MK-8628 elevated the SCLC cell killing by etoposide/carboplatin in 20-25% from the SCLC lines. Only 10-15% from the SCLC lines had an elevated reaction to etoposide/carboplatin when concurrently uncovered towards the PARP inhibitor talazoparib.