Multiple myeloma (MM) is the second most common hematologic malignancy that originates from B-cells (plasma cells) and causes 2% of cancer-related deaths. Symptoms of MM include bone pain caused by multiple osteolytic lesions, pathologic fractures, and hypercalcemia. Typically, MM has a low growth fraction and it is highly dependent on the microenvironment. These properties have made it hard to target by conventional chemotherapy, but could now be exploited by novel stroma-targeting drugs and immunotherapy. These new approaches underline the need for well characterized models with functional immune system and appropriate tumor microenvironment. To gain additional information supporting the use of the syngeneic 5TGM1 murine multiple myeloma model in drug development, we tested drug sensitivity of 5TGM1 cells by screening an extensive panel of drugs.

The compound library consisting of 460 compounds included conventional chemotherapy, kinase inhibitors, metabolic modifiers, rapalogs, differentiating/epigenetic modifiers, kinesin inhibitors, apoptotic modulators, NSAIDs, hormone therapy, immunomodulators and HSP inhibitors. The compounds were tested in five concentrations covering a 10.000-fold drug-relevant concentration range in 384-well format. Cells were seeded to plates with a compound library, followed by cell viability measurements (CellTiter-Glo) after 72 hours. Maximal and minimal responses to drugs were analyzed, and the EC50 values were calculated. Drug Sensitivity Score (DSS) was calculated for each drug as a measure of reduced viability.

According to DSS analysis, 5TGM1 cells showed sensitivity to conventional chemotherapy, such as antimitotic drugs, and kinase inhibitors, such as MEK1/2 inhibitors. In addition, the cells showed particular sensitivity to several HSP90 inhibitors currently in phase I/II clinical development for MM. Lenalidomide and pomalidomide, efficient in treating multiple myeloma in humans, both gave low DSS value indicating that 5TGM1 cells are not sensitive to these drugs, which is expected because they do not bind to murine form of the target cereblon. In contrast, 5TGM1 cells were highly sensitive to the proteasome inhibitor bortezomib (DSS 32.2), which is currently in clinical use.

In conclusion, the murine 5TGM1 cells show sensitivity to various MM drugs used in the clinic and under development. Evaluating the effects of the microenvironment on the growth and drug sensitivity of 5TGM1 cells in vitro and in vivo will be essential. Furthermore, the cell-based compound screening combined with DSS analysis provides a possibility to profile cellular responses to an extensive collection of anti-cancer compounds enabling identification of vulnerabilities in cancer cells and functional investigation of cellular pathways behind drug sensitivity or resistance.

Citation Format: Jenni Mäki-Jouppila, Jenni Bernoulli, Mari I. Suominen, Tiina Kähkönen, Jussi M. Halleen, Sanna Timonen, Elina Huovari, Katja Suomi, Swapnil Potdar, Maria Nurmi, Päivi Östling, Jani Saarela, Katja M. Fagerlund. Drug sensitivity profile of 5TGM1 murine multiple myeloma cell line emphasizes the translational potential of the syngeneic in vivo model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3838. doi:10.1158/1538-7445.AM2017-3838