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Abstract Antibody-drug conjugates (ADCs) that couple the potent anti-mitotic agents monomethyl auristatin E or F (MMAE or MMAF) to tumor antigen specific monoclonal antibodies have demonstrated antitumor activity in preclinical models. We report that the combination of auristatin-based ADCs with inhibitors of the phosphoinositide 3-kinase (PI3K) -AKT-mammalian target of rapamycin (mTOR) signaling pathway improves cytotoxic activity in Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and renal cell carcinoma (RCC) cell line models. Implicated in tumor cell growth and survival, the PI3K-AKT-mTOR pathway is frequently hyperactivated in carcinomas and hematologic malignancies with elevated AKT activity reported in ∼64% of Hodgkin Reed-Sternberg (HRS) cells and 25-52% of primary patient diffuse large B-cell lymphomas. We produced dose response curves for auristatin ADCs and PI3K-AKT-mTOR pathway inhibitors, alone and in combination, and then performed combination index (CI) analysis using the Chou-Talalay method. The CD30-targeting ADC brentuximab vedotin (SGN-35) and the CD19-targeting ADC (SGN-19A) were synergistic (CI 0. 7) with the allosteric mTORC1 inhibitors sirolimus and temsirolimus in panel of lymphoma cell lines. Similarly, a CD70 targeting ADC (SGN-75) was synergistic with sirolimus and temsirolimus in RCC cell lines. Unconjugated MMAE drug was synergistic in combination with sirolimus and temsirolimus, proving the auristatin component of the ADC is responsible for enhanced combinatorial activity. Next, we found that brentuximab vedotin, SGN-19A, and SGN-75 were each synergistic with NVP-BEZ235, a dual specificity PI3K and mTORC1/2 catalytic site inhibitor. Therefore, the synergy observed with auristatin ADCs is generalizable to inhibitors of the PI3K-AKT-mTOR pathway and not unique to rapamycin analogs. Finally, the brentuximab vedotin combination with temsirolimus was evaluated in a L428 mouse xenograft model of B-like HL. Temsirolimus and brentuximab vedotin alone showed antitumor activity in the L428 model; however, the brentuximab vedotin plus temsirolimus combination had significantly greater (P-value = 0. 001) antitumor activity than either drug alone. The mechanism for the synergy observed in these combinations may involve reduced expression of antiapoptotic proteins by mTOR pathway inhibitors, which sensitizes cancer cells to auristatin ADCs. Collectively, these data suggest the potential for auristatin ADC plus mTOR inhibitor cotherapy in PI3K-AKT-mTOR pathway hyperactivated lymphomas and carcinomas. Citation Format: Authors. Abstract title abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71 (8 Suppl): Abstract nr 1789. doi: 10. 1158/1538-7445. AM2011-1789
Lewis et al. (Fri,) studied this question.