Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival

Matthew G. Oser, Raquel Fonseca, Abhishek A. Chakraborty, Rachel Brough, Alexander Spektor, Rebecca B. Jennings, Abdallah Flaifel, Jesse S. Novak, Aditi Gulati, Elizabeth Buss, Scott T. Younger, Samuel K. McBrayer, Glenn S. Cowley, Dennis M. Bonal, Quang De Nguyen, Laura Brulle-Soumare, Paula Taylor, Stefano Cairo, Colm J. Ryan, Elizabeth J. PeaseKim Maratea, Jon Travers, David E. Root, Sabina Signoretti, David Pellman, Susan Ashton, Christopher J. Lord, Simon T. Barry, William G. Kaelin

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1 −/− SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1 −/− SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other RB1 −/− cancers. Significance: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1 −/− SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1 −/− SCLC tumors in mice at nontoxic doses.

Original languageEnglish (US)
Pages (from-to)230-247
Number of pages18
JournalCancer discovery
Volume9
Issue number2
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Aurora Kinase B
Small Cell Lung Carcinoma
Tumor Suppressor Genes
Clustered Regularly Interspaced Short Palindromic Repeats
E2F Transcription Factors
Cell Line
Mutation
Genes
Lung Neoplasms
Neoplasms
Biomarkers

ASJC Scopus subject areas

  • Oncology

Cite this

Oser, M. G., Fonseca, R., Chakraborty, A. A., Brough, R., Spektor, A., Jennings, R. B., ... Kaelin, W. G. (2019). Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival. Cancer discovery, 9(2), 230-247. https://doi.org/10.1158/2159-8290.CD-18-0389

Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival. / Oser, Matthew G.; Fonseca, Raquel; Chakraborty, Abhishek A.; Brough, Rachel; Spektor, Alexander; Jennings, Rebecca B.; Flaifel, Abdallah; Novak, Jesse S.; Gulati, Aditi; Buss, Elizabeth; Younger, Scott T.; McBrayer, Samuel K.; Cowley, Glenn S.; Bonal, Dennis M.; Nguyen, Quang De; Brulle-Soumare, Laura; Taylor, Paula; Cairo, Stefano; Ryan, Colm J.; Pease, Elizabeth J.; Maratea, Kim; Travers, Jon; Root, David E.; Signoretti, Sabina; Pellman, David; Ashton, Susan; Lord, Christopher J.; Barry, Simon T.; Kaelin, William G.

In: Cancer discovery, Vol. 9, No. 2, 01.01.2019, p. 230-247.

Research output: Contribution to journalArticle

Oser, MG, Fonseca, R, Chakraborty, AA, Brough, R, Spektor, A, Jennings, RB, Flaifel, A, Novak, JS, Gulati, A, Buss, E, Younger, ST, McBrayer, SK, Cowley, GS, Bonal, DM, Nguyen, QD, Brulle-Soumare, L, Taylor, P, Cairo, S, Ryan, CJ, Pease, EJ, Maratea, K, Travers, J, Root, DE, Signoretti, S, Pellman, D, Ashton, S, Lord, CJ, Barry, ST & Kaelin, WG 2019, 'Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival', Cancer discovery, vol. 9, no. 2, pp. 230-247. https://doi.org/10.1158/2159-8290.CD-18-0389
Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB et al. Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival. Cancer discovery. 2019 Jan 1;9(2):230-247. https://doi.org/10.1158/2159-8290.CD-18-0389
Oser, Matthew G. ; Fonseca, Raquel ; Chakraborty, Abhishek A. ; Brough, Rachel ; Spektor, Alexander ; Jennings, Rebecca B. ; Flaifel, Abdallah ; Novak, Jesse S. ; Gulati, Aditi ; Buss, Elizabeth ; Younger, Scott T. ; McBrayer, Samuel K. ; Cowley, Glenn S. ; Bonal, Dennis M. ; Nguyen, Quang De ; Brulle-Soumare, Laura ; Taylor, Paula ; Cairo, Stefano ; Ryan, Colm J. ; Pease, Elizabeth J. ; Maratea, Kim ; Travers, Jon ; Root, David E. ; Signoretti, Sabina ; Pellman, David ; Ashton, Susan ; Lord, Christopher J. ; Barry, Simon T. ; Kaelin, William G. / Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival. In: Cancer discovery. 2019 ; Vol. 9, No. 2. pp. 230-247.
@article{b0392ef313674a7bb0261440adeb86ab,
title = "Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival",
abstract = "Small cell lung cancer (SCLC) accounts for 15{\%} of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1 −/− SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1 −/− SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other RB1 −/− cancers. Significance: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1 −/− SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1 −/− SCLC tumors in mice at nontoxic doses.",
author = "Oser, {Matthew G.} and Raquel Fonseca and Chakraborty, {Abhishek A.} and Rachel Brough and Alexander Spektor and Jennings, {Rebecca B.} and Abdallah Flaifel and Novak, {Jesse S.} and Aditi Gulati and Elizabeth Buss and Younger, {Scott T.} and McBrayer, {Samuel K.} and Cowley, {Glenn S.} and Bonal, {Dennis M.} and Nguyen, {Quang De} and Laura Brulle-Soumare and Paula Taylor and Stefano Cairo and Ryan, {Colm J.} and Pease, {Elizabeth J.} and Kim Maratea and Jon Travers and Root, {David E.} and Sabina Signoretti and David Pellman and Susan Ashton and Lord, {Christopher J.} and Barry, {Simon T.} and Kaelin, {William G.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/2159-8290.CD-18-0389",
language = "English (US)",
volume = "9",
pages = "230--247",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival

AU - Oser, Matthew G.

AU - Fonseca, Raquel

AU - Chakraborty, Abhishek A.

AU - Brough, Rachel

AU - Spektor, Alexander

AU - Jennings, Rebecca B.

AU - Flaifel, Abdallah

AU - Novak, Jesse S.

AU - Gulati, Aditi

AU - Buss, Elizabeth

AU - Younger, Scott T.

AU - McBrayer, Samuel K.

AU - Cowley, Glenn S.

AU - Bonal, Dennis M.

AU - Nguyen, Quang De

AU - Brulle-Soumare, Laura

AU - Taylor, Paula

AU - Cairo, Stefano

AU - Ryan, Colm J.

AU - Pease, Elizabeth J.

AU - Maratea, Kim

AU - Travers, Jon

AU - Root, David E.

AU - Signoretti, Sabina

AU - Pellman, David

AU - Ashton, Susan

AU - Lord, Christopher J.

AU - Barry, Simon T.

AU - Kaelin, William G.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1 −/− SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1 −/− SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other RB1 −/− cancers. Significance: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1 −/− SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1 −/− SCLC tumors in mice at nontoxic doses.

AB - Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1 −/− SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1 −/− SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other RB1 −/− cancers. Significance: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1 −/− SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1 −/− SCLC tumors in mice at nontoxic doses.

UR - http://www.scopus.com/inward/record.url?scp=85061276200&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061276200&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-18-0389

DO - 10.1158/2159-8290.CD-18-0389

M3 - Article

C2 - 30373918

AN - SCOPUS:85061276200

VL - 9

SP - 230

EP - 247

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 2

ER -