Identifying Lethal Dependencies with HUGE Predictive Power

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Abstract
Recent functional genomic screens—such as CRISPR-Cas9 or RNAi screening—have fostered a new wave of targeted treatments based on the concept of synthetic lethality. These approaches identified LEthal Dependencies (LEDs) by estimating the effect of genetic events on cell viability. The multiple-hypothesis problem is related to a large number of gene knockouts limiting the statistical power of these studies. Here, we show that predictions of LEDs from functional screens can be dramatically improved by incorporating the “HUb effect in Genetic Essentiality” (HUGE) of gene alterations. We analyze three recent genome-wide loss-of-function screens—Project Score, CERES score and DEMETER score—identifying LEDs with 75 times larger statistical power than using state-of-the-art methods. Using acute myeloid leukemia, breast cancer, lung adenocarcinoma and colon adenocarcinoma as disease models, we validate that our predictions are enriched in a recent harmonized knowledge base of clinical interpretations of somatic genomic variants in cancer (AUROC > 0.87). Our approach is effective even in tumors with large genetic heterogeneity such as acute myeloid leukemia, where we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal dependencies of either NRAS or PTPN11 depending on the NRAS mutational status. HUGE will hopefully help discover novel genetic dependencies amenable for precision-targeted therapies in cancer. All the graphs showing lethal dependencies for the 19 tumor types analyzed can be visualized in an interactive tool.
Funding Information
  • Provincial Council of Gipuzkoa (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Instituto de Salud Carlos III (ISCIII) (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • TRANSCAN EPICA (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • TRANSCAN EPICA (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Minister of Economy and Competitiveness of Spain (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • PIBA Programme of the Basque Government (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Cancer Research UK (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • CIBERONC (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Spanish Ministry of Economy, Industry and Competitivity (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Gobierno de Navarra, Departamento de Salud (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Departamento de Industria (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • RETOS Investigacion Referencia (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)
  • Basque Government (PI14/01867, PI16/02024, PI17/00701, PI19/01352, PI20/01306, AC16/00041, AC16/00041, PID2019-110344RB-I00, PIBA_2020_01_0055, C355/A26819, CB16/12/00489, RTHALMY SAF2017-92632-EXP, 40/2016, PID2019-110344RB-I00, PRE_2016_1_0194)

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