TY - JOUR

T1 - In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance

AU - Wirth, Anna-Katharina

AU - Wange, Lucas

AU - Vosberg, Sebastian

AU - Henrich, Kai-Oliver

AU - Rausch, Christian

AU - Özdemir, Erbey

AU - Zeller, Christina M

AU - Richter, Daniel

AU - Feuchtinger, Tobias

AU - Kaller, Markus

AU - Hermeking, Heiko

AU - Greif, Philipp A

AU - Senft, Daniela

AU - Jurinovic, Vindi

AU - Bahrami, Ehsan

AU - Jayavelu, Ashok Kumar

AU - Westermann, Frank

AU - Mann, Matthias

AU - Enard, Wolfgang

AU - Herold, Tobias

AU - Jeremias, Irmela

N1 - © 2022. The Author(s).

PY - 2022

Y1 - 2022

N2 - Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.

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

KW - Humans

KW - Mice

KW - Animals

KW - CRISPR-Cas Systems

KW - Antineoplastic Agents/therapeutic use

KW - Neoplasms/genetics

KW - Disease Models, Animal

KW - Transcriptome

KW - Xenograft Model Antitumor Assays

U2 - 10.1038/s41375-022-01726-7

DO - 10.1038/s41375-022-01726-7

M3 - Journal article

C2 - 36333584

VL - 36

SP - 2863

EP - 2874

JO - Leukemia

JF - Leukemia

SN - 0887-6924

ER -