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Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Cell | 2018

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.

Pubmed ID: 29681454 RIS Download

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R35 CA197717
  • Agency: NCI NIH HHS, United States
    Id: R35 CA220449
  • Agency: NCI NIH HHS, United States
    Id: P30 CA142543
  • Agency: NCI NIH HHS, United States
    Id: P30 CA016058
  • Agency: NCI NIH HHS, United States
    Id: P50 CA070907
  • Agency: NCI NIH HHS, United States
    Id: U01 CA176284
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM008203
  • Agency: NCI NIH HHS, United States
    Id: T32 CA124334

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This is a list of tools and resources that we have found mentioned in this publication.


BD FACSDiva Software (tool)

RRID:SCR_001456

A collection of tools for flow cytometer and application setup, data acquisition, and data analysis that help streamline flow cytometry workflows. It provides features to help users integrate flow systems into new application areas, including index sorting for stem cell and single-cell applications, as well as automation protocols for high-throughput and robotic laboratories.

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Cytoscape (tool)

RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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Pfam (tool)

RRID:SCR_004726

A database of protein families, each represented by multiple sequence alignments and hidden Markov models (HMMs). Users can analyze protein sequences for Pfam matches, view Pfam family annotation and alignments, see groups of related families, look at the domain organization of a protein sequence, find the domains on a PDB structure, and query Pfam by keywords. There are two components to Pfam: Pfam-A and Pfam-B. Pfam-A entries are high quality, manually curated families that may automatically generate a supplement using the ADDA database. These automatically generated entries are called Pfam-B. Although of lower quality, Pfam-B families can be useful for identifying functionally conserved regions when no Pfam-A entries are found. Pfam also generates higher-level groupings of related families, known as clans (collections of Pfam-A entries which are related by similarity of sequence, structure or profile-HMM).

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BD Biosciences (tool)

RRID:SCR_013311

An Antibody supplier

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Glucose Transporter GLUT1 antibody (antibody)

RRID:AB_305540

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Anti-CRISPR-Cas9 antibody (antibody)

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HES1 (D6P2U) (antibody)

RRID:AB_2728766

This monoclonal targets HES1

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Glucocorticoid Receptor (D6H2L) XP® Rabbit mAb (antibody)

RRID:AB_2631286

This monoclonal targets Glucocorticoid Receptor

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Glucose Transporter 8 antibody (antibody)

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This polyclonal targets Glucose Transporter 8 antibody

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Nrf2 Recombinant Polyclonal Antibody (21HCLC) (antibody)

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This recombinant polyclonal targets Nrf2

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Cyclin D1 Antibody (antibody)

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This polyclonal targets Ccnd1

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CYP4F11 (F21 P6 F5) (antibody)

RRID:AB_2088410

This monoclonal targets Human CYP4F11

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K-Ras (F234) (antibody)

RRID:AB_627865

This monoclonal targets KRAS

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Lamin B1 (D4Q4Z) Rabbit mAb #12586 (antibody)

RRID:AB_2650517

This monoclonal targets Lamin B1

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GAPDH (D16H11) XP Rabbit mAb (antibody)

RRID:AB_10622025

This monoclonal targets GAPDH

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ZR-75-1 (cell line)

RRID:CVCL_0588

Cell line ZR-75-1 is a Cancer cell line with a species of origin Homo sapiens (Human)

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UACC-812 (cell line)

RRID:CVCL_1781

Cell line UACC-812 is a Cancer cell line with a species of origin Homo sapiens (Human)

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T-47D (cell line)

RRID:CVCL_0553

Cell line T-47D is a Cancer cell line with a species of origin Homo sapiens (Human)

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SK-BR-3 (cell line)

RRID:CVCL_0033

Cell line SK-BR-3 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-361 (cell line)

RRID:CVCL_0620

Cell line MDA-MB-361 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MCF-7 (cell line)

RRID:CVCL_0031

Cell line MCF-7 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-468 (cell line)

RRID:CVCL_0419

Cell line MDA-MB-468 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-453 (cell line)

RRID:CVCL_0418

Cell line MDA-MB-453 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-436 (cell line)

RRID:CVCL_0623

Cell line MDA-MB-436 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-231 (cell line)

RRID:CVCL_0062

Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-157 (cell line)

RRID:CVCL_0618

Cell line MDA-MB-157 is a Cancer cell line with a species of origin Homo sapiens (Human)

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Hs 578T (cell line)

RRID:CVCL_0332

Cell line Hs 578T is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC70 (cell line)

RRID:CVCL_1270

Cell line HCC70 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC202 (cell line)

RRID:CVCL_2062

Cell line HCC202 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1937 (cell line)

RRID:CVCL_0290

Cell line HCC1937 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1806 (cell line)

RRID:CVCL_1258

Cell line HCC1806 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1569 (cell line)

RRID:CVCL_1255

Cell line HCC1569 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1500 (cell line)

RRID:CVCL_1254

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HCC1419 (cell line)

RRID:CVCL_1251

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RRID:CVCL_1249

Cell line HCC1395 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1187 (cell line)

RRID:CVCL_1247

Cell line HCC1187 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1428 (cell line)

RRID:CVCL_1252

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HCC1143 (cell line)

RRID:CVCL_1245

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BT-483 (cell line)

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BT-474 (cell line)

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