Details

Autor(en) / Beteiligte

• Ham, Jungoh
• Costa, Carlotta
• Sano, Renata
• Lochmann, Timothy L.
• Sennott, Erin M.
• Patel, Neha U.
• Dastur, Anahita
• Gomez-Caraballo, Maria
• Krytska, Kateryna
• Hata, Aaron N.
• Floros, Konstantinos V.
• Hughes, Mark T.
• Jakubik, Charles T.
• Heisey, Daniel A.R.
• Ferrell, Justin T.
• Bristol, Molly L.
• March, Ryan J.
• Yates, Craig
• Hicks, Mark A.
• Nakajima, Wataru
• Gowda, Madhu
• Windle, Brad E.
• Dozmorov, Mikhail G.
• Garnett, Mathew J.
• McDermott, Ultan
• Harada, Hisashi
• Taylor, Shirley M.
• Morgan, Iain M.
• Benes, Cyril H.
• Engelman, Jeffrey A.
• Mossé, Yael P.
• Faber, Anthony C.

Titel

Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination

Ist Teil von

• Cancer cell, 2016-02, Vol.29 (2), p.159-172

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression. [Display omitted] •Amplified MYCN is synthetic lethal with the BCL-2 inhibitor ABT-199 in neuroblastoma•MYCN upregulates the MCL-1 inhibitor, NOXA•MYCN-amplified neuroblastomas are further sensitized to ABT-199 with MLN8237•ABT-199 with MLN8237 induce tumor regressions in MYCN-amplified neuroblastoma mice Ham et al. show that MYCN-amplified neuroblastomas are sensitive to treatment with the BCL-2 inhibitor ABT-199 due to MYCN-driven increase of NOXA. Combination treatment with the Aurora Kinase A inhibitor MLN8237 and ABT-199 is synergistic in xenograft models of this tumor type, in part via reducing MCL-1.