A framework for target discovery in rare cancers.

While large-scale functional genetic screens have uncovered numerous cancer dependencies, rare cancers are poorly represented in such efforts and the landscape of dependencies in many rare cancers remains obscure. We performed genome-scale CRISPR knockout screens in an exemplar rare cancer, TFE3 -translocation renal cell carcinoma (tRCC), revealing previously unknown tRCC-selective dependencies in pathways related to mitochondrial biogenesis, oxidative metabolism, and kidney lineage specification. To generalize to other rare cancers in which experimental models may not be readily available, we employed machine learning to infer gene dependencies in a tumor or cell line based on its transcriptional profile. By applying dependency prediction to alveolar soft part sarcoma (ASPS), a distinct rare cancer also driven by TFE3 translocations, we discovered and validated that MCL1 represents a dependency in ASPS but not tRCC. Finally, we applied our model to predict gene dependencies in tumors from the TCGA (11,373 tumors; 28 lineages) and multiple additional rare cancers (958 tumors across 16 types, including 13 distinct subtypes of kidney cancer), nominating potentially actionable vulnerabilities in several poorly-characterized cancer types. Our results couple unbiased functional genetic screening with a predictive model to establish a landscape of candidate vulnerabilities across cancers, including several rare cancers currently lacking in potential targets.
Competing Interests: Aspects of this work are the subject of a pending patent application (A.S., S.R.V.). S.R.V.: has consulted for Jnana Therapeutics within the past 3 years; receives research support from Bayer. T.K.C. reports institutional and personal paid or unpaid support for research, advisory board participation, consultancy, and honoraria within the past 5 years from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan and Precede Bio, Novartis, Oncohost, Pfizer, Roche, Sanofi Aventis, Scholar Rock, Surface Oncology, Takeda, and Tempest and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, and Primium.