# Targeting mutated MYD88 signaling in WM

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2020 · $419,976

## 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 models for translation to clin...

## Key facts

- **NIH application ID:** 9994198
- **Project number:** 5P50CA100707-17
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** STEVEN PETER TREON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,976
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994198

## Citation

> US National Institutes of Health, RePORTER application 9994198, Targeting mutated MYD88 signaling in WM (5P50CA100707-17). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9994198. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*