Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer.
Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hyun Seok
HS
Kim
Saurabh
S
Mendiratta
Jiyeon
J
Kim
Chad Victor
CV
Pecot
Jill E
JE
Larsen
Iryna
I
Zubovych
Bo Yeun
BY
Seo
Jimi
J
Kim
Banu
B
Eskiocak
Hannah
H
Chung
Elizabeth
E
McMillan
Sherry
S
Wu
Jef
J
De Brabander
Kakajan
K
Komurov
Jason E
JE
Toombs
Shuguang
S
Wei
Michael
M
Peyton
Noelle
N
Williams
Adi F
AF
Gazdar
Bruce A
BA
Posner
Rolf A
RA
Brekken
Anil K
AK
Sood
Ralph J
RJ
Deberardinis
Michael G
MG
Roth
John D
JD
Minna
Michael A
MA
White
D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D020756:Coatomer Protein / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D011905:Genes, ras; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009368:Neoplasm Transplantation; D010085:Oxidative Phosphorylation; D014227:Triazines / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D020756:Coatomer Protein; D007211:Indoles; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C585392:SW044248; D014227:Triazines