Patient-derived models of acquired resistance can identify effective drug combinations for cancer.
Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Adam S
AS
Crystal
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Alice T
AT
Shaw
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Lecia V
LV
Sequist
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Luc
L
Friboulet
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Matthew J
MJ
Niederst
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Elizabeth L
EL
Lockerman
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Rosa L
RL
Frias
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Justin F
JF
Gainor
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Arnaud
A
Amzallag
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Patricia
P
Greninger
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Dana
D
Lee
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Anuj
A
Kalsy
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Maria
M
Gomez-Caraballo
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Leila
L
Elamine
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Emily
E
Howe
Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, MA 02115, USA. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791, South Korea.
Wooyoung
W
Hur
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Eugene
E
Lifshits
Massachusetts General Hospital Cancer Center, Department of Pathology and Harvard Medical School, Boston, MA 02114, USA.
Hayley E
HE
Robinson
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Ryohei
R
Katayama
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Anthony C
AC
Faber
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Mark M
MM
Awad
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
Sridhar
S
Ramaswamy
Massachusetts General Hospital Cancer Center, Department of Pathology and Harvard Medical School, Boston, MA 02114, USA.
Mari
M
Mino-Kenudson
Massachusetts General Hospital Cancer Center, Department of Pathology and Harvard Medical School, Boston, MA 02114, USA.
A John
AJ
Iafrate
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA. jengelman@partners.org cbenes@partners.org.
Cyril H
CH
Benes
Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA. jengelman@partners.org cbenes@partners.org.
Jeffrey A
JA
Engelman
D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D066230:Patient-Specific Modeling; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D013450:Sulfones / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; C496365:FGFR3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D016392:Proto-Oncogene Proteins pp60(c-src); D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C586847:ceritinib