Ji Luo, Ph.D.
Our long-term research goals are to understand the biology of the Ras oncogene and identify new therapeutic strategies for Ras mutant tumors. Each year, more than 130,000 patients in the US are diagnosed with cancer with Ras mutations; yet few targeted therapies are effective for these tumors. To better understand how mutant KRAS promotes tumor initiation, tumor maintenance and metastasis, we are investigating how oncogene and non-oncogene addiction pathways cooperatively support the malignant phenotype of KRAS mutant cells. We are dissecting the role of oncogenic stress response including SUMOylation, autophagy and metabolic adaptation in supporting the viability of KRAS mutant colorectal, lung and pancreatic cancer cells. We use a multi-disciplinary approach that integrates functional genomics, systems biology, transcriptomics, proteomics, signal transduction and chemical biology to probe genetic dependencies in KRAS mutant cells. In addition, we are developing new CRISPR gene editing tools and pharmacological tools to identify and validate druggable targets and target combinations in KRAS mutant cells. Ultimately, we aim to translate our discoveries in cancer research into better treatment outcomes for cancer patients.
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.
Selected Recent Publications
- PNAS. doi: 10.1073/pnas.1817494116. [Epub ahead of print]: 2019. [ Journal Article ]
- Nucleic Acids Research. 45(11):e101: 2017. [ Journal Article ]
CRISPR/Cas9-mediated gene knockout is insensitive to target copy number but is dependent on guide RNA potency and Cas9/sgRNA threshold expression level..Nucleic Acids Research. 45(20):12039-12053: 2017. [ Journal Article ]
- PNAS. 112(14):E1724-33: 2015. [ Journal Article ]
- Cancer Discovery. 4(10): 1182-1197, 2014. [ Journal Article ]
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.
|Fehad Khan||Postbaccalaureate Fellow (CRTA)|
|Chih-Shia Lee Ph.D.||Research Fellow|
|Shinjen (Sean) Lin Ph.D.||Postdoctoral Fellow (CRTA)|
|Xiang Wang Ph.D.||Special Volunteer|
|Haibo Zhang Ph.D.||Postdoctoral Fellow (Visiting)|