TY - JOUR
T1 - A framework for identification of actionable cancer genome dependencies in small cell lung cancer
AU - Sos, Martin L.
AU - Dietlein, Felix
AU - Peifer, Martin
AU - Schoẗtle, Jakob
AU - Balke-Want, Hyatt
AU - Mul̈ler, Christian
AU - Koker, Mirjam
AU - Richters, André
AU - Heynck, Stefanie
AU - Malchers, Florian
AU - Heuckmann, Johannes M.
AU - Seidel, Danila
AU - Eyers, Patrick A.
AU - Ullrich, Roland T.
AU - Antonchick, Andrey P.
AU - Vintonyak, Viktor V.
AU - Schneider, Peter M.
AU - Ninomiya, Takashi
AU - Waldmann, Herbert
AU - Buẗtner, Reinhard
AU - Rauh, Daniel
AU - Heukamp, Lukas C.
AU - Thomas, Roman K.
PY - 2012/10/16
Y1 - 2012/10/16
N2 - Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.
AB - Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.
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U2 - 10.1073/pnas.1207310109
DO - 10.1073/pnas.1207310109
M3 - Article
C2 - 23035247
AN - SCOPUS:84867627577
SN - 0027-8424
VL - 109
SP - 17034
EP - 17039
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -
