Evidence map›Paper›PMID 31925410›Full record

ArticleNature structural & molecular biology2020

Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

N S Persky, D Hernandez, M Do Carmo, L Brenan, O Cohen, S Kitajima, U Nayar, A Walker, S Pantel, Y Lee and 13 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature structural & molecular biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed, 1 pooled it
2.7field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

37 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 3 institutions in 1 country.

N S PerskyThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
D Hernandez *The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
M Do Carmo *The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
L Brenan *The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
O CohenThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
S KitajimaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
U NayarThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
A WalkerThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
S PantelThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Y LeeThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
J CordovaUniversity of New Mexico, Albuquerque, NM, USA.
M SathappaThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
C ZhuThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
T K HayesThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
P RamThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
P PancholiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
T S MikkelsenThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
D A BarbieDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
X YangThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
R HaqDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-1290-9276
F PiccioniThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1210-3210
D E RootThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-5122-861X
C M JohannessenThe Broad Institute of MIT and Harvard, Cambridge, MA, USA. johannes@broadinstitute.org.ORCID http://orcid.org/0000-0002-2618-1036
Broad Institute · USHarvard University · USUniversity of New Mexico · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

Indexed as

Drug ResistancePoint MutationAdenosine TriphosphateAmino Acid SequenceAnimalsDrug DiscoveryDrug Resistance, NeoplasmHumansModels, MolecularNeoplasmsProtein Kinase InhibitorsProtein KinasesProteomicsAdenosine TriphosphateProtein Kinase InhibitorsProtein Kinases

Identifiers

PMID31925410
OpenAlexW2998796208

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.