# Characterizing the landscape of resistance and persistence mechanisms in CML

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $329,175

## Abstract

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by a (9;22) translocation, which
generates the constitutively active BCR-ABL1 tyrosine kinase. BCR-ABL1 is the critical mediator of disease
pathogenesis, exhibiting constitutive kinase activity that drives survival and proliferation through multiple
downstream pathways. While therapy with the ABL1 kinase inhibitor imatinib leads to durable responses in the
majority of patients with chronic phase CML, a substantial number of patients develop resistance to therapy,
and transient responses are the rule for patients with more advanced disease. Resistance is commonly due to
acquired point mutations in the BCR-ABL1 kinase domain, and the second-generation ABL1 inhibitors nilotinib,
dasatinib, bosutinib, and ponatinib are largely effective salvage therapies in this therapeutic scenario.
However, recent clinical reports suggest that sequential treatment with single agent ABL1 kinase inhibitor
therapy can select for BCR-ABL1 compound mutants (two mutations within the same BCR-ABL1 molecule)
that confer high-level resistance to multiple inhibitors. In vitro biochemical and cell-based resistance screens,
along with crystallographic studies, will be used to better characterize and determine treatment strategies for
controlling BCR-ABL1 compound mutations and to minimize the risk of their emergence. Beyond BCR-ABL1
kinase domain mutations, a subset of patients exhibit disease progression via BCR-ABL1 kinase-independent
mechanisms, the underlying causative molecular events of which are considerably more heterogeneous and
have not been comprehensively characterized. The combination of functional screens using panels of small-
molecule inhibitors with whole exome and RNA sequencing analysis will be used to accelerate the
identification of molecular mechanisms of BCR-ABL1 kinase-independent resistance. Lastly, despite the utility
of ABL1 kinase inhibitor therapies in the management of CML, growing evidence suggests that inhibition of
BCR-ABL1 kinase activity in CML stem cells is insufficient to eliminate these cells, thus requiring even the best
responding patients to remain on therapy life-long. To develop strategies for selectively targeting CML disease
persistence, small-molecule inhibitor-based combinations simultaneously blocking BCR-ABL1 and either
bolstering phosphatase activity or inhibiting MEK/ERK-regulated auxiliary signaling will be evaluated in primary
CML specimens using a variety of ex vivo cellular, biochemical, and flow cytometric methods. Thus, this
proposal centers on: 1) establishment of strategies for controlling and preventing the emergence of
highly-resistant BCR-ABL1 compound mutations, 2) elucidation of molecular lesions and
therapeutically actionable pathways mediating BCR-ABL1 kinase-independent resistance, and 3)
evaluation of mechanisms to selectively eliminate persistent CML stem cells. This knowledge will inform
and improve the disease management for patients...

## Key facts

- **NIH application ID:** 9833484
- **Project number:** 5R01CA065823-24
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** BRIAN J DRUKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,175
- **Award type:** 5
- **Project period:** 1995-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833484

## Citation

> US National Institutes of Health, RePORTER application 9833484, Characterizing the landscape of resistance and persistence mechanisms in CML (5R01CA065823-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9833484. Licensed CC0.

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