# Investigating paradoxical YAP activation as an emergent limitation to Cu chelation therapy in BRAF V600E-driven melanoma

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $22,320

## Abstract

PROJECT SUMMARY
Melanoma is the most lethal subtype of skin cancer with a high frequency of BRAF mutations. Over 90% of
BRAF mutations are V600E, which results in hyperactivation of the mitogen-activated protein kinase (MAPK)
pathway. Patients with metastatic melanoma have minimal therapeutic options and responses to current
strategies targeting BRAF and/or MEK1/2 kinases are only transient due to the emergence of drug resistance.
Our lab has identified Cu as a novel vulnerability within the MAPK pathway that can be leveraged to induce
antineoplastic activity in BRAFV600E melanomas. Cu binding to MEK1/2 is required for kinase activity, and
lowering Cu levels reduced tumorigenesis in a murine model of BRAFV600E metastatic melanoma. While Cu is
traditionally thought of as a structural or catalytic cofactor for enzymatic reactions, a newfound role in modulating
kinase activity has brought another layer of regulation to signaling pathways that can be further studied and
potentially targeted in therapeutic strategies. Interestingly, a Cu chelator, tetrathiomolybdate (TTM), both
synergized with inhibitors of BRAF and MEK1/2 and showed effectiveness in inhibitor resistant melanoma cells.
However, similar to BRAF and MEK1/2 inhibitors, the response to Cu chelation is cytostatic and short-term and
thus, elucidation of additional Cu-dependent kinases may unlock other mechanisms of TTM that can propel this
drug to be a more efficacious therapeutic option for late-stage BRAF-driven melanoma. In studying Cu
dependent kinases, we identified large tumor suppressor 1/2 (LATS1/2) as targets of Cu chelation. LATS1/2 are
integral kinases involved in mediating cell growth within the Hippo pathway. Inhibition of LATS1/2 upregulate
oncogenic Yes- associated protein (YAP). Conversely, LATS1/2 are phosphorylated and activated by upstream
kinases enabling LATS1/2 to phosphorylate YAP, preventing its nuclear localization. Enhanced YAP nuclear
accumulation is observed in cancers including BRAFV600E-mutant melanoma, where it is active to initiate a
growth-promoting transcriptional program. Aside from phosphorylation, additional modulators of LATS1/2 kinase
activity are unknown. We found that Cu chelation inhibits LATS1/2 kinase activity in vitro and that LATS1/2 bind
Cu. However, it is not clear whether Cu is necessary for LATS1/2 kinase activity in vivo. While Cu chelation
inhibits oncogenic MAPK signaling, I hypothesize that Cu is needed for LATS1/2 kinase activity and that
concomitant inhibition of LATS1/2 will dampen the Hippo pathway, consequently limiting the efficacy of Cu
chelation therapy. In Aim 1, I will define the specific Cu binding sites within LATS1/2 to assess the contribution
of Cu to LATS1/2 kinase activity in BRAFV600E mutant melanoma cell lines. In Aim 2, I will use genetic and
pharmacologic means to co-target YAP and Cu in murine models of melanoma to assess the efficacy of the
combination therapy in a BRAFV600E mutant setting and further test this regi...

## Key facts

- **NIH application ID:** 9982040
- **Project number:** 5F31CA243294-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Tiffany Tsang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,320
- **Award type:** 5
- **Project period:** 2019-07-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982040

## Citation

> US National Institutes of Health, RePORTER application 9982040, Investigating paradoxical YAP activation as an emergent limitation to Cu chelation therapy in BRAF V600E-driven melanoma (5F31CA243294-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982040. Licensed CC0.

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