# Inhibition of brain metastasis by blocking MAPK12 driver kinase functions

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $432,573

## Abstract

Among 1.6 million women diagnosed with breast cancer every year, about 10-16% develop brain metastasis.
Even with the most advanced clinical care, patients with brain metastasis have a devastating <20% one-year
survival. At present, no effective drug treatment exists for patients with refractory breast cancer metastatic to
the brain. Therefore, novel and effective therapies are urgently needed for this population. Unfortunately,
developing effective therapies for brain metastasis is largely hampered by a lack of in-depth understanding of
the basic mechanisms of brain metastasis, which could guide drug development and clinical trials. To
surmount the challenge, we have performed an unprecedented in vivo screen of the human kinome to uncover
novel kinases that promote breast cancer brain metastasis in mice, because kinases are at the central nodes
of cancer cell signaling networks critical for cancer progression/metastasis and are druggable as therapeutic
targets. Among the top candidate kinases associated with aggressive brain metastasis we identified, Mitogen-
Activated Protein Kinase 12 (MAPK12, also known as p38γ) was not previously known to play roles in brain
metastasis but is overexpressed in highly aggressive human breast cancers, and patients with MAPK12 high-
expressing breast cancers have higher incidences of brain metastasis later on. Therefore, we performed
experimental brain metastasis assays using MAPK12-overexpressing breast cancer cells, and validated that
MAPK12 indeed promotes brain metastasis in animals. MAPK12 is a member of the MAPK family and its
overexpression increases cancer cell motility and invasion. Excitingly, we identified that MAPK12 is located at
the "hub" of a signaling network of brain metastasis-enriched kinases that enhances brain metastatic cells’
utilization of lactate as an energy source for outgrowth in the brain. Furthermore, MAPK12 is targetable with
available inhibitors that are used in the clinic for other diseases. Here, we hypothesize that activation/
overexpression of MAPK12 coordinates signaling pathways in breast cancer cells to promote brain metastasis,
and MAPK12 may be effectively inhibited by using clinically applicable kinase inhibitors. The major goals of
this proposal are 1) Determine the functional roles of MAPK12 in spontaneous brain metastasis and in immune
competent brain metastasis models, and further validating their clinical relevance; 2) Investigate novel
mechanisms of MAPK12-mediated breast cancer brain metastasis by focusing on how MAPK12-activated
brain metastatic cancer cells efficiently use lactate as an energy source for adaptation and outgrowth in the
brain; 3) Explore the potential of MAPK12 as a therapeutic target for the treatment and/or prevention of breast
cancer brain metastasis. The successful completion of these studies will bring about new understanding of
breast cancer brain metastasis and the first generation of effective brain metastasis-targeted therapies.
Ultimate...

## Key facts

- **NIH application ID:** 10172862
- **Project number:** 5R01CA208213-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Dihua Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,573
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172862

## Citation

> US National Institutes of Health, RePORTER application 10172862, Inhibition of brain metastasis by blocking MAPK12 driver kinase functions (5R01CA208213-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10172862. Licensed CC0.

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