Non-Oncogene Addiction and Synthetic Lethality in KRAS Mutant Cancer
We have previously conducted RNAi screens to identify synthetic lethal partners of the KRAS oncogene (Luo et al., Cell, 2009). Our recent efforts have focused on understanding the molecular mechanisms by which non-oncogene addition pathways support KRAS-driven oncogenesis. In particular, we have elucidated the mechanisms by which the RNA splicing factor ERH (Weng et al., PNAS, 2012), the protein SUMOyltation pathway (Yu et al., PNAS, 2015) and the autophagy pathway (Lee et al., PNAS, 2019) support the viability of KRAS mutant cells. Our studies indicate that KRAS mutant cells exhibit non-oncogene addiction to a broad network of genes that act to alleviate oncogenic stress. We are exploring how our discoveries can be translated with small-molecule inhibitors that target non-oncogene addiction pathways to selectively eliminate cancer cells.
Dissection of Genetic Dependencies in KRAS Mutant Cells
We have developed a combinatorial RNAi platform that can co-target up to seven genes simultaneously in the cell to understand Ras effector and oncogenic stress response pathway cooperativity (Yuan et al., Cancer Discovery, 2014). This unique approach has enabled us to systematically interrogate the pattern of oncogene and non-oncogene addiction in KRAS mutant cells. We have optimized the CRISPR/Cas9 genome editing tools to enable genetic screens using flexible gene knockout libraries (Yuen et al., NAR, 2017 and Read et al., NAR 2017). We have utilized this platform to identify genes that play important roles in oncogenic transformation and in drug resistance.
Rational Drug Combinations in KRAS Mutant Cells
We are investigating new therapeutic modalities against KRAS mutant cancer. We have developed a pharmacological synthetic lethal screen to identify drug combinations that show selective toxicity in KRAS mutant cells. We are using PROTAC and other chemical biology approaches to validate drug targets and target combinations.
Trainee positions: To inquire about potential post-doctoral and post-baccalaureate trainee positions, please e-mail a cover letter and CV to Dr. Luo.
Ji Luo received his B.A. in Natural Sciences from the University of Cambridge, UK in 1998. He completed his Ph.D. training as an HHMI Predoctoral Fellow in the laboratory of Dr. Lewis Cantley at Harvard University, Boston. His Ph.D. research focused on the role of PI 3-kinase in development, diabetes and cancer. Ji Luo undertook his postdoctoral training as an AACR Fellow in the laboratory of Dr. Stephen Elledge at Harvard Medical School, Boston. His postdoctoral research focused on the development of bar-coded shRNA library technologies for genome-wide RNAi synthetic lethal analysis in cancer cells. He received tenure at NIH in 2019.
- Read A, Gao S, Batchelor E, Luo J. Flexible CRISPR library construction using parallel oligonucleotide retrieval. Nucleic Acids Res. 2017;45(11):e101.
- Yu B, Swatkoski S, Holly A, Lee LC, Giroux V, Lee CS, Hsu D, Smith JL, Yuen G, Yue J, Ann DK, Simpson RM, Creighton CJ, Figg WD, Gucek M, Luo J. Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proc Natl Acad Sci U S A. 2015;112(14):E1724-33.
- Yuan TL, Fellmann C, Lee CS, Ritchie CD, Thapar V, Lee LC, Hsu DJ, Grace D, Carver JO, Zuber J, Luo J, McCormick F, Lowe SW. Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discov. 2014;4(10):1182-1197.
- Weng MT, Lee JH, Wei SC, Li Q, Shahamatdar S, Hsu D, Schetter AJ, Swatkoski S, Mannan P, Garfield S, Gucek M, Kim MK, Annunziata CM, Creighton CJ, Emanuele MJ, Harris CC, Sheu JC, Giaccone G, Luo J. Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells. Proc Natl Acad Sci U S A. 2012;109(52):E3659-67.
- Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell. 2009;137(5):835-48.
Related Scientific Focus Areas
Genetics and Genomics
This page was last updated on Friday, September 15, 2023