# RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $12,467

## Abstract

RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis
ABSTRACT: Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause
of morbidity and mortality of PC, imposing significant social and economic burdens. Three recent phase III clinical
trials (i.e., SPARTAN, PROSPER, and ARAMIS) unequivocally demonstrated that preventing or delaying PC
metastasis provides strong clinical benefits, prolonging the median overall survival by 10-14 months. To keep
up the momentum and further improve the metastasis-free survival (a strong surrogate of overall survival) of PC
patients, there is an urgent unmet need to identify novel druggable targets in PC metastasis and delineate their
mechanisms of action (MoAs). Through an integrated analysis of three clinical omics databases, we identified
receptor-interacting protein kinase 2 (RIPK2) as a top druggable target candidate for PC metastasis. RIPK2 is
amplified/gained in 65% of lethal metastatic castration-resistant PC and its mRNA overexpression is associated
with disease progression and poor prognosis. RIPK2 knockout (RIPK2-KO) or treatment with a potent RIPK2
inhibitor (e.g., the FDA-approved ponatinib) significantly suppressed PC cell invasion and colony formation but
not proliferation in vitro and reduced the metastasis of 22Rv1 cells by up to 92% in vivo. Mechanistically, distinct
from the canonical NOD/RIPK2/NF-κB pathway, RIPK2 strongly regulates the stability and activity of c-Myc (a
driver of PC metastasis), largely by binding and activating MKK7, which we identified as a novel direct c-Myc-
S62 kinase. This noncanonical RIPK2/MKK7/c-Myc signaling pathway can be potently inactivated by RIPK2-KO
or ponatinib and thus is a very promising drug target in PC metastasis. Here, our overall goal is to provide a
strong scientific rationale for a clinical trial by testing a central hypothesis: RIPK2/MKK7/c-Myc signaling is
associated with PC progression, metastasis, and poor prognosis in patients and is critical for RIPK2-dependent
PC metastasis, and its inhibition is the primary (albeit not the only) MoA of ponatinib in suppressing PC
metastasis. The PI has assembled an outstanding multi-disciplinary team to pursue three distinct but interrelated
specific aims: 1) assess the clinical correlations and refine the molecular basis of RIPK2/MKK7/c-Myc signaling,
2) determine whether RIPK2-KO inhibits PC metastasis primarily by inactivating the MKK7/c-Myc signaling
pathway, and 3) determine whether ponatinib impairs PC metastasis primarily by inactivating RIPK2/MKK7/c-
Myc signaling and define RIPK2-independent MoAs of ponatinib in suppressing PC metastasis. If successful,
the proposed studies will expose a novel Achilles’ heel for PC metastasis and reveal the major MoAs of RIPK2-
KO and ponatinib in suppressing PC metastasis. They will provide valuable preclinical data to guide the
development of a clinical trial repurposing ponatinib to substantially impro...

## Key facts

- **NIH application ID:** 10686235
- **Project number:** 5R01CA266694-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Wei Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $12,467
- **Award type:** 5
- **Project period:** 2022-08-18 → 2023-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686235

## Citation

> US National Institutes of Health, RePORTER application 10686235, RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis (5R01CA266694-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10686235. Licensed CC0.

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