Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.
There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Joan
J
Montero
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Kristopher A
KA
Sarosiek
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Joseph D
JD
DeAngelo
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ophélia
O
Maertens
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Jeremy
J
Ryan
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Dalia
D
Ercan
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Huiying
H
Piao
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Neil S
NS
Horowitz
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ross S
RS
Berkowitz
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Ursula
U
Matulonis
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Pasi A
PA
Jänne
Hematology/Oncology Department of Medicine, Massachusetts General Hospital, Boston, MA 02114,USA.
Philip C
PC
Amrein
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Karen
K
Cichowski
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ronny
R
Drapkin
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: anthony_letai@dfci.harvard.edu.
Anthony
A
Letai
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D057285:Precision Medicine; D015398:Signal Transduction