# Oncogenic tyrosine kinases inhibitors abrogate DNA repair and sensitive leukemias to PARP inhibitors

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $376,152

## Abstract

Oncogenic tyrosine kinases (OTKs) such as FLT3(ITD) and JAK2(V617F) induce acute myeloid
leukemia (AML) and myeloproliferative neoplasms (MPNs), respectively. OTKs may be
accompanied by “additional” mutations (e.g., TET2, DNMT3A) complicating genetic/epigenetic
signature. Selective OTK inhibitors (OTKi) are developed against FLT3(ITD)-positive AMLs and
JAK2(V617F)-positive MPNs, but complete remissions were rare in OTKi-treated patients, and
after initial response the disease progressed often in to more malignant stage.
 FLT3(ITD)-positive AMLs and JAK2(V617F)-positive MPNs accumulate lethal DNA double-
strand breaks (DSBs). DSBs are repaired by two major mechanisms, BRCA-mediated
homologous recombination (HR) and DNA-PK –mediated non-homologous end-joining (D-
NHEJ). HR and D-NHEJ repair DSBs in proliferating cells and D-NHEJ plays a major role in
quiescent cells. PARP1–dependent back-up NHEJ (B-NHEJ) works in proliferating and
quiescent cells. FLT3(ITD) and JAK2(V617F)-positive AML/MPN stem cells are usually resistant
to DSBs because these OTKs modulate DNA repair pathways to promote survival.
 Cancer-specific defects in DSB repair create the opportunity to employ synthetic lethality,
e.g. elimination of BRCA1/2-mutated cancer cells by PARP inhibitor (PARPi). We reported that
OTKis induce HR and D-NHEJ deficiencies, which sensitize quiescent and proliferating
FLT3(ITD)/JAK2(V617F)-positive AML/MPN stem cells to synthetic lethality triggered by PARPi.
 However, our recent reports and preliminary data strongly suggest that “additional”
mutations (e.g., in TET2, DNMT3A) can change FLT3(ITD) and JAK2(V617F)-positive
AML/MPN cells sensitivity to OTKi + PARPi. Therefore in Specific Aim #1 we propose to identify
“additional” mutations and mechanisms which affect sensitivity of FLT3(ITD) and JAK2(V617F)-
positive cells to OTKi+PARPi-mediated synthetic lethality.
 We also reported and obtained preliminary data that bone marrow microenvironment (BMM)
induces resistance to OTKi + PARPi treatment. Therefore we will pinpoint BMM-related
obstacles for OTKi + PARPi-mediated synthetic lethality and apply BMM inhibitor (BMMi) in
Specific Aim #2: Overcoming the protective effect of BMM against OTKi + PARPi treatment.
 Finally, we will test therapeutic potential of OTKi + PARPi +/- BMMi against AMLs/MPNs
xenografts carrying mutations favoring synthetic lethal effect in Specific Aim #3. Therapeutic
effect of OTKi + PARPi +/- BMMi against AMLs/MPNs carrying specific “driver” mutations
[FLT3(ITD/TKD), JAK2(V617F)] and “additional” mutations (e.g., TET2).

## Key facts

- **NIH application ID:** 10114255
- **Project number:** 5R01CA244044-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** TOMASZ SKORSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,152
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114255

## Citation

> US National Institutes of Health, RePORTER application 10114255, Oncogenic tyrosine kinases inhibitors abrogate DNA repair and sensitive leukemias to PARP inhibitors (5R01CA244044-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114255. Licensed CC0.

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