# Targeting a Novel Signaling Nexus pACK/pCSK/pLCK in Immune Checkpoint Blockade (ICB)-Resistant Prostate Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $460,148

## Abstract

Project Abstract
Prostate cancer (PC) patient although initially respond to androgen deprivation therapy, most patients develop
the resistance developing a stage referred to as the Castration Resistant Prostate Cancer (CRPC). Prostate
cancer is a non-inflamed or “Immune desert” tumor where no immune infiltrate is observed, suggesting that
failure has occurred somewhere in the process of T-cell priming, or T-cell trafficking back to the tumor. Not
surprisingly, prostate cancer is highly refractory to immune checkpoint blockade (ICB) therapies exhibiting
marginal efficacy in clinical trials, both as a single agent or in combination with other agents. Precisely how
prostate cancer enforce evasion of anti-tumor immune response is not fully understood.
Previously, we uncovered that a non-receptor tyrosine kinase, ACK1 deposited novel pY88-H4 epigenetic marks
in AR gene enhancer, regulating AR/AR-V7 expression. Building on this discovery, we developed a new ACK1
small molecule inhibitor, (R)-9b, which suppressed enzalutamide-resistant tumor growth. To examine ACk1
signaling further, we generated a viable conditional ACK1 knockout (KO) mice, and noticed a significant increase
in activated CD4+ and CD8+ T cells in KO mice, causing loss of syngeneic prostate tumor growth.
The subsequent studies have revealed a crucial role for ACK1 kinase in the initiation of T cell antigen
receptor (TCR) signaling by phosphorylation of CSK at a previously unknown site, Tyr18. CSK phosphorylated
LCK at Tyr505 promoting auto-inhibition, inhibiting an adaptive immune response. Thus, ACK1 KO mice, or the
(R)-9b injected mice exhibited increased CD4+ and CD8+ T cells activation and inhibition of tumor growth. In
addition, (R)-9b functionally reinvigorated peripheral blood mononuclear cells (PBMCs) of the CRPC patients to
mount robust immune response against CRPC organoids. Together, these data indicate that (R)-9b fulfills a
unique niche, wherein it not only suppresses AR/AR-V7 within the tumor cells, but also activates host immune
system to mount a robust `dual’ anti-tumor response. The specific aims of this project are:
Aim 1: Examine roles of ACK1-mediated CSK Tyr18-phosphorylation in T cell quiescence
Aim 2: Interrogate role of renewed pACK1/pY18-CSK/pY505-LCK signaling in silencing of anti-tumor immune
response
Aim 3: Evaluate therapeutic efficacy of (R)-9b in models of prostate cancer

## Key facts

- **NIH application ID:** 10876452
- **Project number:** 5R01CA276502-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nupam P Mahajan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,148
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876452

## Citation

> US National Institutes of Health, RePORTER application 10876452, Targeting a Novel Signaling Nexus pACK/pCSK/pLCK in Immune Checkpoint Blockade (ICB)-Resistant Prostate Cancer (5R01CA276502-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10876452. Licensed CC0.

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