# Mechanisms of MEK/ERK growth arrest signaling

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $308,000

## Abstract

The Raf/MEK/ERK pathway is frequently deregulated in cancer, thus being a key target for therapy.
Although recent development of advanced inhibitors targeting B-Raf and MEK1/2 has improved therapy of
B-RafV600E,K melanoma, the ability of these tumors to develop drug resistance and the intrinsic resistance of
many other MEK/ERK-deregulated tumor types to these inhibitors demand additional therapeutic strategies.
Because tumor cells have the ability to develop drug resistances by reactivating MEK/ERK via genetic
alterations or feedback rearrangement of the associated signaling network, it is predicted that current
therapeutic strategies aiming MEK/ERK inhibition will be continuously challenged. Given that, one promising
strategy would be to exploit a weakness(s) of cancer cells, which is inevitably associated with their aberrant
MEK/ERK activity. The goal of this project is to determine whether mortalin (GRP75/HSPA9), a molecular
chaperone in the HSP70 family, can be targeted to selectively induce mitochondria-driven death
mechanisms in MEK/ERK-deregulated tumor cells. In the previous funding period, we discovered that
mortalin upregulation in cancer is a key mechanism that facilitates MEK/ERK-mediated tumor cell
proliferative signaling by suppressing the pathway’s potential to trigger growth arrest. In an effort to further
elaborate mortalin functions in cancer, we discovered that mortalin can also facilitate tumor cell survival by
regulating mitochondrial bioenergetics. This latter function of mortalin needs to be thoroughly evaluated in
the context of MEK/ERK signaling because the data from our preliminary studies strongly suggest that
mortalin deprivation can selectively induce robust cell death in tumor cells exhibiting aberrant MEK/ERK
activity, including the B-RafV600E tumor cells that have acquired resistance to B-Raf inhibitors. Moreover, our
data suggest that mortalin depletion induces cell death in MEK/ERK-deregulated tumor cells by regulating
adenine nucleotide translocases (ANT) and voltage-dependent anion channel (VDAC), the mitochondrial
channels that are critical for cellular bioenergetics but can also turn into powerful death machinery when
stressed. We therefore hypothesize that a key function of mortalin is to protect tumor cells from
mitochondrial bioenergetics stress caused by aberrant MEK/ERK activity. By extension, we predict that
mortalin provides a unique target to selectively trigger mitochondrial death mechanisms in MEK/ERK-
deregulated tumor cells. To test these hypotheses, Aim 1 will determine whether mortalin regulates cell
death/survival via ANT/VDAC-associated mitochondrial permeability transition and Ca2+ flux from ER to
mitochondria. Aim 2 will determine whether mortalin suppresses mitochondrial cell death caused by
bioenergetics stress in MEK/ERK-deregulated tumor cells. Aim 3 will determine whether mortalin targeting
can effectively suppress MEK/ERK-deregulated tumors in vivo. The obtained results will help defin...

## Key facts

- **NIH application ID:** 9970208
- **Project number:** 5R01CA138441-10
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Jong-In Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2010-07-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970208

## Citation

> US National Institutes of Health, RePORTER application 9970208, Mechanisms of MEK/ERK growth arrest signaling (5R01CA138441-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970208. Licensed CC0.

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