# Targeting mutated MYD88 signaling in WM

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2021 · $471,278

## Abstract

PROJECT SUMMARY 
By whole genome sequencing, we discovered highly recurring MYD88 mutations in 95-97% of Waldenstrom's 
macroglobulinemia (WM) patients that promote constitutive pro-survival NF-kB activation through 
IRAK1/IRAK4 and BTK. These findings enabled us to perform a pivotal clinical trial that led to the approval of 
the BTK inhibitor ibrutinib for WM by the U.S. FDA, and EMA. Despite high response rates, most responses to 
ibrutinib are partial, and persistent IRAK1/IRAK4 signaling appears responsible for this intrinsic resistance to 
ibrutinib. We therefore propose in these studies to create inducible knockdown mutants of IRAK1, IRAK4 and 
both IRAK1 and IRAK4 in MYD88 mutated WM cell lines to clarify the importance of IRAK1 vs. IRAK4, vs. both 
in mediating pro-survival signaling. We will also perform replacement experiments by transduction of kinase 
intact or kinase dead IRAK1 and IRAK4 to clarify the importance of scaffold versus kinase mediated pro- 
survival signaling. The findings from these experiments will guide development of highly selective and potent 
prototype inhibitors of IRAK1 (JH-X- 119-01) and IRAK1/IRAK4 (JH-I-25) that we have manufactured. Based 
on guidance from knockdown experiments, we will optimize the pharmacokinetic and pharmacodynamic 
properties of the lead inhibitor for use in human studies, and will delineate its pharmacological consequences 
as a single agent and in combination with ibrutinib in WM cells dependent on mutated MYD88 growth and 
survival signaling. Acquired resistance to ibrutinib is also an emerging problem in WM patients. We recently 
identified BTKCys481 mutations that abrogate ibrutinib-BTK binding in samples from half of WM patients who 
progressed on ibrutinib, and showed that transduction of the most common BTK mutation (BTKCys481Ser) led 
to activation of ERK1/2 survival signaling, inflammatory cytokine production, and ibrutinib resistance in MYD88 
mutated WM cells. In recent work, we identified HCK, a SRC family member that is down-regulated at later 
stages of B-cell ontogeny, as an important component of mutated MYD88 survival signaling that activates BTK, 
as well as AKT and ERK1/2. We propose in these studies to delineate the importance of HCK blockade to 
overcoming acquired ibrutinib resistance mediated by mutated BTKCys481. In pursuit of this aim, we have 
developed highly potent and selective prototype HCK kinase inhibitors from two distinct scaffolds (SB1-G-33 
and A419259) that show potent cytotoxic, HCK and BTK inhibition in BTKCys481 mutated WM cells. We 
propose to optimize these molecules to achieve potent target engagement, pharmacokinetic, and 
pharmacodynamic properties suitable for human studies, and delineate the pharmacological consequences of 
the lead HCK kinase inhibitor in BTKCys481 expressing ibrutinib resistant primary WM cells, and WM cell 
lines. We will validate the lead IRAK and HCK inhibitors developed in these studies using our in vivo WM 
rodent m...

## Key facts

- **NIH application ID:** 10194390
- **Project number:** 5P50CA100707-18
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** STEVEN PETER TREON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $471,278
- **Award type:** 5
- **Project period:** 2003-09-16 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194390

## Citation

> US National Institutes of Health, RePORTER application 10194390, Targeting mutated MYD88 signaling in WM (5P50CA100707-18). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10194390. Licensed CC0.

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