In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance

• DOI: 10.1038/s41375-022-01726-7
• Publication Date: 2022-11-04T16:04:58Z
• Authors: Anna-Katharina Wirth; Lucas Wange; Sebastian Vosberg; Kai-Oliver Henrich; Christian Rausch; Erbey Özdemir; Christina M. Zeller; Daniel Richter; Tobias Feuchtinger; Markus Kaller; Heiko Hermeking; Philipp A. Greif; Daniela Senft; Vindi Jurinovic; Ehsan Bahrami; Ashok Kumar Jayavelu; Frank Westermann; Matthias Mann; Wolfgang Enard; Tobias Herold; Irmela Jeremias
• Keywords: 0301 basic medicine; 0303 health sciences; Antineoplastic Agents; Xenograft Model Antitumor Assays; Article; 3. Good health; Mice; Disease Models, Animal; 03 medical and health sciences; Neoplasms; Humans; Animals; CRISPR-Cas Systems; Transcriptome

Abstract Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of patients. To gain mechanistic insights, we developed model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) acute lymphoblastic leukemia with widely-used cytotoxic drugs 18 consecutive weeks. In two distinct PDX samples, tumors initially responded treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, different mutations in TP53 individual sets chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven combination stochastic deterministic processes. Transcriptome proteome showed shared dysregulations providing putative targets overcome resistance. vivo CRISPR/Cas9 dropout screens revealed broad dependency on BCL2 , BRIP1 COPS2 . Accordingly, venetoclax re-sensitized derivative chemotherapy, despite genomic heterogeneity, demonstrating direct translatability the approach. Hence, presence multiple resistance-associated effective rescue polychemotherapy-resistant can be identified using functional testing preclinical models.