# Androgen receptor function in melanoma

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $457,178

## Abstract

Abstract
Malignant melanoma is an example of primary clinical significance for investigating sex-related
differences in cancer arising in organs with non-reproductive functions. Differences in sex
hormone levels and in downstream pathways are likely to play a key role, which is however still
poorly understood. Our main working hypothesis is that androgen receptor (AR) and associated
proteins converge on control of melanoma development and response to treatment. In recent
work, we have found that genetic and pharmacological suppression of AR activity in a large panel
of melanoma cells reduces self-renewal potential and tumorigenesis, inducing double strand DNA
damage and cytoplasmic leakage, a STING-dependent pro-inflammatory cascade and a gene
expression signature associated with better patients' survival. Based on further preliminary data,
we will test two specific hypotheses: 1) AR signaling plays a key role in melanoma cells at the
intersection between gene transcription and DNA repair / genomic stability with nuclear lamins as
co-determinants. We will probe into the biochemical and functional significance of endogenous
AR-lamin interactions and AR-dependent lamin A/C association with the PPP1 protein
phosphatase, impinging on lamin phosphorylation at critical residues, and with the DDX3X and
DDX3Y RNA helicases, encoded by X- and Y-linked genes and with expression of prognostic
significance for female and male patients, respectively. 2) Targeting AR is of translational
significance for preventing / counteracting resistance of melanomas with BRAFv600 mutations to
BRAF inhibitors (BRAFi). In preliminary work, we found striking up-regulation of AR expression in
response to BRAFi, proliferation and tumorigenesis of BRAFi resistant melanoma cells are
suppressed by AR inhibition, AR overexpression is by itself sufficient to confer BRAFi resistance.
In further studies we will assess to what extent suppression of AR expression and activity has an
impact on melanoma cell subpopulations with intrinsic BRAFi resistance and/or BRAFi-induced
epigenetic reprogramming. We will analyze a collection of freshly derived cells from Patient-
Derived Xenografts (PDX) of BRAFi sensitive and resistant melanomas and assess to what extent
the beneficial effects of suppression of AR signalling occur in vivo, restoring one or more aspects
of the BRAFi response of the corresponding PDXs.

## Key facts

- **NIH application ID:** 10416658
- **Project number:** 1R01CA269356-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GIAN-PAOLO DOTTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $457,178
- **Award type:** 1
- **Project period:** 2022-09-23 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416658

## Citation

> US National Institutes of Health, RePORTER application 10416658, Androgen receptor function in melanoma (1R01CA269356-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10416658. Licensed CC0.

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