TAK-243 Combined With Radiation And Other DNA Damaging Agents As A Novel Therapeutic Strategy For Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) (∼15-17% of lung cancer) is an aggressive disease, with a dismal overall five-year survival of 7%. The current first-line therapy consisting of cisplatin and etoposide chemotherapy (C/E) +/- radiation (RT), has changed minimally in >30 years. TAK-243, an E1 ubiquitin activating enzyme (UAE) inhibitor, is a promising novel SCLC therapy. TAK-243 limits the formation of ubiquitin conjugates that mediate many cellular processes including DNA repair signaling. By dysregulating cancer-specific dependencies of UAE, TAK-243 may induce malignant cell death and potentiate DNA damage induced by RT and chemotherapeutic agents. Initial findings show TAK-243 is particularly effective for 2 SCLC cell-lines (EC50 of 0.006 - 0.011mM), compared to other cancers and normal tissues (n = 29, EC50 ranging from 0.012 to 1.31mM; Hyer et al., 2018). However, TAK-243 has not been comprehensively evaluated as a single agent or in combination with C/E and RT for SCLC. SCLC cell-lines were treated with incremental doses of TAK-243 (0-1mM) and viability was determined by a resazurin conversion assay after 6 days. EC50 values were compared. To evaluate combination effects, C/E were administered (1:1 ratio, 0-1mM) to cell-lines together with a fixed cell-line specific TAK-243 dose (EC30). Area under the curve (AUC) was compared between TAK-243+C/E and C/E-alone groups. TAK-243 (0-1mM) was administered with RT (2-8 Gy) in a similar manner and cell viability was measured after 9 days. Dose modification factor (DMF), the ratio of RT dose required between control and drug-treated groups, was calculated at survival fraction 37. TAK-243 single agent therapy (20mg/kg, BIW) was evaluated in a patient-derived xenograft (PDX) SCLC model (SCRX-Lu149). Subcutaneous tumors were established, and tumor volumes were compared between experimental and control conditions. Kaplan-Meier survival analysis and significance testing using the Log-Rank Test were completed. Single-agent therapy. EC50 values of SCLC cell-lines (n = 11) ranged from 0.003-0.12mM in vitro. TAK-243-treated animals experienced significantly increased freedom from volumetric endpoint (p-value = 0.028) when evaluated in vivo. TAK-243+Chemotherapy. Treatment revealed a positive combination effect for the majority of SCLC cell-lines (n = 5, ΔAUC from -13-47 units), suggesting potential chemosensitivity. TAK-243+Radiotherapy. Potential radiosensitization was observed in all SCLC cell-lines (n = 5) as tested by the resazurin assay (DMF from 1.25-1.35). Cell-line and PDX models of SCLC are sensitive to TAK-243. With TAK-243, lower doses of C/E and RT are required for most cell-lines. Use of TAK-243 may be a novel strategy to improve SCLC therapies. These findings will be validated using clonogenic survival assays and interrogated in vivo, which may provide a basis to move TAK-243 to the clinic.