XSystematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer

Hyun Seok Kim, Saurabh Mendiratta, Jiyeon Kim, Chad Victor Pecot, Jill E. Larsen, Iryna Zubovych, Bo Yeun Seo, Jimi Kim, Banu Eskiocak, Hannah Chung, Elizabeth McMillan, Sherry Wu, Jef De Brabander, Kakajan Komurov, Jason E. Toombs, Shuguang Wei, Michael Peyton, Noelle Williams, Adi F. Gazdar, Bruce A. Posner & 6 others Rolf A. Brekken, Anil K. Sood, Ralph J. Deberardinis, Michael G. Roth, John D. Minna, Michael A. White

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalCell
Volume155
Issue number3
DOIs
StatePublished - Oct 24 2013

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Non-Small Cell Lung Carcinoma
Tumors
Cells
Coat Protein Complex I
Cytology
Inflammasomes
Neoplasms
Gene expression
Mutation
Screening
Genetic Testing
Chemical activation
Transcriptome
Cell Biology
Lung
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

XSystematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. / Kim, Hyun Seok; Mendiratta, Saurabh; Kim, Jiyeon; Pecot, Chad Victor; Larsen, Jill E.; Zubovych, Iryna; Seo, Bo Yeun; Kim, Jimi; Eskiocak, Banu; Chung, Hannah; McMillan, Elizabeth; Wu, Sherry; De Brabander, Jef; Komurov, Kakajan; Toombs, Jason E.; Wei, Shuguang; Peyton, Michael; Williams, Noelle; Gazdar, Adi F.; Posner, Bruce A.; Brekken, Rolf A.; Sood, Anil K.; Deberardinis, Ralph J.; Roth, Michael G.; Minna, John D.; White, Michael A.

In: Cell, Vol. 155, No. 3, 24.10.2013.

Research output: Contribution to journalArticle

Kim, HS, Mendiratta, S, Kim, J, Pecot, CV, Larsen, JE, Zubovych, I, Seo, BY, Kim, J, Eskiocak, B, Chung, H, McMillan, E, Wu, S, De Brabander, J, Komurov, K, Toombs, JE, Wei, S, Peyton, M, Williams, N, Gazdar, AF, Posner, BA, Brekken, RA, Sood, AK, Deberardinis, RJ, Roth, MG, Minna, JD & White, MA 2013, 'XSystematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer', Cell, vol. 155, no. 3. https://doi.org/10.1016/j.cell.2013.09.041
Kim, Hyun Seok ; Mendiratta, Saurabh ; Kim, Jiyeon ; Pecot, Chad Victor ; Larsen, Jill E. ; Zubovych, Iryna ; Seo, Bo Yeun ; Kim, Jimi ; Eskiocak, Banu ; Chung, Hannah ; McMillan, Elizabeth ; Wu, Sherry ; De Brabander, Jef ; Komurov, Kakajan ; Toombs, Jason E. ; Wei, Shuguang ; Peyton, Michael ; Williams, Noelle ; Gazdar, Adi F. ; Posner, Bruce A. ; Brekken, Rolf A. ; Sood, Anil K. ; Deberardinis, Ralph J. ; Roth, Michael G. ; Minna, John D. ; White, Michael A. / XSystematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. In: Cell. 2013 ; Vol. 155, No. 3.
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abstract = "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.",
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AU - Posner, Bruce A.

AU - Brekken, Rolf A.

AU - Sood, Anil K.

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