# Epigenetic mechanisms of transcriptional activation of a novel oncogenic ALK variant in cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $488,718

## Abstract

Abstract
Comprehensive genomic characterization in cancer has revolutionized our understanding of cancer
pathogenesis and provided the scientific rationale for the clinical success of targeted therapies in a variety of
cancers. There is emerging evidence that oncogenes activated through epigenetic mechanisms are also
important in oncogenic transformation and can dictate therapeutic responses. We recently discovered a novel
oncogenic ALK variant, ALKATI, arising through alternative transcription initiation independent of genetic
alteration, in 3.4% of all TCGA cancers, including 12% of melanomas and less frequently in other cancer types.
The ALKATI can stimulate multiple signaling pathways and is capable of driving oncogenic transformation in
immortalized cells in vitro and drive tumorigenesis in vivo. Moreover, engineered ALKATI-transformed cells and
tumors, and ALKATI-positive patient derived cell lines and xenografts are sensitive to ALK inhibitors. A patient
with ALKATI-positive advanced melanoma who has progressed on standard of care systemic therapy and
investigational combination immunotherapy of nivolumab and ipilimumab derived significant clinical benefit
from Crizotinib (an ALK inhibitor) with tumor shrinkage and improvement in quality of life. These data have
provided the scientific rationale and enthusiasm for the current clinical investigations of ALK-targeted therapies
in therapeutic refractory advanced melanoma.
ALKATI is not expressed in normal tissues. It is biallelically expressed in tumor samples. These observations,
together with the lack of somatic mutations at the ALK locus in the ALKATI-positive tumor samples, indicate that
the ALKATI transcriptional activation is through epigenetic mechanisms. Our preliminary data further indicate
that MAPK signaling regulates ALKATI expression. Here, we proposes systematic and comprehensive
investigations focused on understanding the epigenetic mechanisms in the following three aims: 1) Define the
three-dimensional chromatin organization of the long-range interacting elements with the ALKATI transcriptional
start site (the ALK-ATI site); 2) Identify and characterize the chromatin modifier(s) involved in ALKATI
transcriptional regulation; 3) Elucidate the regulatory mechanisms of ALKATI expression by MAPK signaling in
melanoma. We will use modern technologies, including RNA-seq, ChIP-seq, 4C-seq, CRISPR, CRISPR
interference (CRISPRi) systems, bioinformatics and integrative analyses, and a repertoire of well-characterized
ALKATI-positive and ALKATI-negative cell lines for the proposed multidisciplinary studies. We anticipate that
these mechanistic studies will provide insight on not only the basic epigenetic mechanisms in oncogene
transcriptional activation through alternative transcription initiation in cancer, but also novel epigenetic
therapeutic strategies to target the oncogene transcriptional activation through similar mechanisms.

## Key facts

- **NIH application ID:** 10394271
- **Project number:** 5R01CA228216-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ping Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $488,718
- **Award type:** 5
- **Project period:** 2018-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394271

## Citation

> US National Institutes of Health, RePORTER application 10394271, Epigenetic mechanisms of transcriptional activation of a novel oncogenic ALK variant in cancer (5R01CA228216-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10394271. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*