Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.
BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; acfaber@vcu.edu jengelman@partners.org.
Anthony C
AC
Faber
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
Anna F
AF
Farago
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Carlotta
C
Costa
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Anahita
A
Dastur
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Maria
M
Gomez-Caraballo
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
Rebecca
R
Robbins
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
Bethany L
BL
Wagner
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
William M
WM
Rideout
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Charles T
CT
Jakubik
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Jungoh
J
Ham
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Elena J
EJ
Edelman
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Hiromichi
H
Ebi
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Alan T
AT
Yeo
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Aaron N
AN
Hata
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Youngchul
Y
Song
Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
Neha U
NU
Patel
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Ryan J
RJ
March
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Ah Ting
AT
Tam
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Randy J
RJ
Milano
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Jessica L
JL
Boisvert
Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
Mark A
MA
Hicks
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
Sarah
S
Elmiligy
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
Scott E
SE
Malstrom
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.
Miguel N
MN
Rivera
Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
Hisashi
H
Harada
Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
Brad E
BE
Windle
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Sridhar
S
Ramaswamy
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
Cyril H
CH
Benes
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
Tyler
T
Jacks
Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; acfaber@vcu.edu jengelman@partners.org.
Jeffrey A
JA
Engelman
D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005818:Genetic Engineering; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012074:Remission Induction; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579095:MCL1 protein, human; D008565:Membrane Proteins; D009025:Morpholines; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C528561:navitoclax
BH3 mimetics; BIM; apoptosis; small-cell lung cancer; targeted therapies