Synthetic lethality-mediated precision oncology via the tumor transcriptome

Joo Sang Lee; Nishanth Ulhas Nair; Gal Dinstag; Lesley Chapman; Youngmin Chung; Kun Wang; Sanju Sinha; Hongui Cha; Dasol Kim; Alexander V. Schperberg; Ajay Srinivasan; Vladimir Lazar; Eitan Rubin; Sohyun Hwang; Raanan Berger; Tuvik Beker; Ze'ev Ronai; Sridhar Hannenhalli; Mark R. Gilbert; Razelle Kurzrock; Se Hoon Lee; Kenneth Aldape; Eytan Ruppin

doi:10.1016/j.cell.2021.03.030

Synthetic lethality-mediated precision oncology via the tumor transcriptome

Joo Sang Lee^*, Nishanth Ulhas Nair, Gal Dinstag, Lesley Chapman, Youngmin Chung, Kun Wang, Sanju Sinha, Hongui Cha, Dasol Kim, Alexander V. Schperberg, Ajay Srinivasan, Vladimir Lazar, Eitan Rubin, Sohyun Hwang, Raanan Berger, Tuvik Beker, Ze'ev Ronai, Sridhar Hannenhalli, Mark R. Gilbert, Razelle KurzrockSe Hoon Lee, Kenneth Aldape, Eytan Ruppin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients’ response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.

Original language	English
Pages (from-to)	2487-2502.e13
Journal	Cell
Volume	184
Issue number	9
DOIs	https://doi.org/10.1016/j.cell.2021.03.030
State	Published - 29 Apr 2021
Externally published	Yes

Funding

Funders	Funder number
Pangea Therapeutics
Sanna Madan
National Institutes of Health
National Cancer Institute	ZIABC011802
National Cancer Institute
Genentech
EMD Serono
Sungkyunkwan University
National Research Foundation of Korea	NRF-2020R1A2C2007652
National Research Foundation of Korea
Institute for Information and Communications Technology Promotion
Ministry of Science and ICT, South Korea	2019-0-00421
Ministry of Science and ICT, South Korea

Keywords

cancer immunotherapy
patient stratification
precision oncology
synthetic lethality
synthetic rescues
transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2021.03.030

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Lee, J. S., Nair, N. U., Dinstag, G., Chapman, L., Chung, Y., Wang, K., Sinha, S., Cha, H., Kim, D., Schperberg, A. V., Srinivasan, A., Lazar, V., Rubin, E., Hwang, S., Berger, R., Beker, T., Ronai, Z., Hannenhalli, S., Gilbert, M. R., ... Ruppin, E. (2021). Synthetic lethality-mediated precision oncology via the tumor transcriptome. Cell, 184(9), 2487-2502.e13. https://doi.org/10.1016/j.cell.2021.03.030

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abstract = "Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients{\textquoteright} response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.",

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Lee, JS, Nair, NU, Dinstag, G, Chapman, L, Chung, Y, Wang, K, Sinha, S, Cha, H, Kim, D, Schperberg, AV, Srinivasan, A, Lazar, V, Rubin, E, Hwang, S, Berger, R, Beker, T, Ronai, Z, Hannenhalli, S, Gilbert, MR, Kurzrock, R, Lee, SH, Aldape, K & Ruppin, E 2021, 'Synthetic lethality-mediated precision oncology via the tumor transcriptome', Cell, vol. 184, no. 9, pp. 2487-2502.e13. https://doi.org/10.1016/j.cell.2021.03.030

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AU - Srinivasan, Ajay

AU - Lazar, Vladimir

AU - Rubin, Eitan

AU - Hwang, Sohyun

AU - Berger, Raanan

AU - Beker, Tuvik

AU - Ronai, Ze'ev

AU - Hannenhalli, Sridhar

AU - Gilbert, Mark R.

AU - Kurzrock, Razelle

AU - Lee, Se Hoon

AU - Aldape, Kenneth

AU - Ruppin, Eytan

PY - 2021/4/29

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Synthetic lethality-mediated precision oncology via the tumor transcriptome

Abstract

Funding

Keywords

UN SDGs

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