Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset.
Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).


CONCLUSIONS
We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses.
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Brinton
B
Seashore-Ludlow
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Matthew G
MG
Rees
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Jaime H
JH
Cheah
Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
Murat
M
Cokol
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Edmund V
EV
Price
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Matthew E
ME
Coletti
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Victor
V
Jones
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Nicole E
NE
Bodycombe
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Christian K
CK
Soule
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Joshua
J
Gould
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Benjamin
B
Alexander
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Ava
A
Li
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Philip
P
Montgomery
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Mathias J
MJ
Wawer
Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
Nurdan
N
Kuru
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Joanne D
JD
Kotz
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
C Suk-Yee
CS
Hon
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Benito
B
Munoz
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Ted
T
Liefeld
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Vlado
V
Dančík
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Joshua A
JA
Bittker
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Michelle
M
Palmer
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts. Cancer Biology and Medical Oncology, Harvard Medical School, Boston, Massachusetts.
James E
JE
Bradner
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts. pclemons@broadinstitute.org stuart_schreiber@harvard.edu ashamji@broadinstitute.org.
Alykhan F
AF
Shamji
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts. pclemons@broadinstitute.org stuart_schreiber@harvard.edu ashamji@broadinstitute.org.
Paul A
PA
Clemons
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Stuart L
SL
Schreiber
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D066264:Datasets as Topic; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054852:Small Molecule Libraries
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries