Drug Sensitivity Is Genotype-Dependent: Study

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Genetically defined mouse models of AEL could help researchers find novel treatment approaches.
Genetically defined mouse models of AEL could help researchers find novel treatment approaches.
The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

SAN DIEGO — Response to individual drugs was found to be associated with cancer genotype, according to a new study, and the model provided a powerful platform for therapeutic intervention and guidance for preclinical drug studies.

Eleven tumors representative of key acute erythroid leukemia (AEL) genotypes from established models of the disease were selected to explore drug sensitivity to 192 therapeutic agents, including conventional chemotherapeutic agents, and compounds targeting epigenetic regulators, protein kinases and cell-cycle checkpoints. Results of this study were presented as a plenary session at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.1

“We successfully generated by CRISPR-Cas9 genetically defined models of AEL, recapitulating the diverse mutational spectra identified in patients,” speaker Ilaria Iacobucci, PhD, St. Jude Children's Research Hospital, Memphis, Tennessee, commented during the presentation.

The final goal of the group's study, according to Dr Iacobucci, was to translate genomic results from mouse models into finding effective therapies for AEL and identifying different alterations that promote oncogenesis.

AEL is a rare form of acute myeloid leukemia (AML) that is typically secondary to myelodysplastic syndrome or chemotherapy and affects less than 5% of adult AML cases.

Researchers used CRISPR-Cas9 genome editing to induce combinations of loss-of-function mutations in recurrently mutated genes in AEL (Tp53, Tet2, Dnmt3a, Asxl1, Ezh2, Stag2, Bcor, Ppm1d, Rb1 and Nfix) to find out what genetic alterations drive AEL. The researchers used a mouse model of disease and performed a comparative genomic analysis of 159 AEL and 1509 non-AEL myeloid tumors.

Single-guide RNA (sgRNA) were used to make leukemic clones from primary tumors, and the investigators established tumors in irradiated congenic mice. The mice were monitored over time for leukemia development, and established tumors were then analyzed.

Results showed that drug sensitivity is associated with leukemia genotype: co-mutated Tet2/Dnmt3a T-cell acute lymphoblastic leukemia cells were sensitive to bromodomain and histone methyltransferase inhibitors, and co-mutated Bcor/Tp53/Dnmt3a or Bcor/Rb1 AEL cells were linked to CDK9 inhibitors (novel inhibitor LY2857785). Finally, Dr Iacobucci noted that Tp53 was “chemoresistant to a wide variety of compounds, but was highly sensitive to different classes of PARP inhibitors, specifically talazoparib.” And, the group was able to subsequently confirm that sensitivity to talazoparib in vivo.

Furthermore, deep targeting by next-generation sequencing confirmed that CRISPR-Cas9–induced genome editing is stable across serial transplants; however, the whole-exome sequencing showed accumulation of CRISPR-Cas9–induced mutations.

“We successfully generated genetically defined models of AEL, demonstrated the role of Tp53 and Bcor mutations in driving the erythroid phenotype, and showed that sensitivity to different classes of compounds is genotype-dependent. These results provide the rationale for testing new targeted agents in AEL,” the team wrote in the abstract that was released prior to their presentation.

Tp53 and recurrent mutations are important players, driving leukemogenesis in the erythroid phenotype, and drug sensitivity is mutational-pattern–dependent,” added Dr Iacobucci. “In conclusion, AEL is characterized by distinct age-related genomic subtypes, with different outcomes.”

Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. For a complete list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor's coverage of the ASH 2018 meeting by visiting the conference page.

Reference

  1. Iacobucci I, Varotto E, Chunxu Qu, et al. Multiplex CRISPR/Cas9-based genome editing of mouse hematopoietic stem cells recapitulates acute erythroid leukemia and identifies therapeutic targets. Oral presentation at: Annual Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 5.

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