# Exploiting POU2F3 addiction in the tuft cell variant of small cell lung cancer

> **NIH NIH U01** · COLD SPRING HARBOR LABORATORY · 2022 · $430,416

## Abstract

Project Summary
Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, which is associated with a high mitotic
rate, early metastatic spread, and a rapid evolution of chemotherapy resistance. We recently discovered a novel
form of SCLC that resembles the tuft cell lineage, which can be distinguished from the classical neuroendocrine
form of this disease through immunohistochemical staining of POU2F3. Importantly, we have identified several
molecular vulnerabilities that are specific to the variant form of this disease. In this research proposal, we seek
to advance personalized therapies that exploit the unique lineage program present in the tuft cell variant of SCLC.
Our innovative functional genomics strategy has already uncovered actionable dependencies that are unique to
tuft cell variant of SCLC, such as the kinase IGF1R. In addition, we discovered a profound addiction of tuft cell
variant SCLC tumors to POU2F3. Here we will investigate the molecular basis of POU2F3 addiction in SCLC,
with the explicit intent to develop small molecules that interfere with POU2F3 function. The first Aim of this
proposal will build upon the extensive epigenomic analyses we have performed in SCLC, which has defined a
unique enhancer landscape sustained by POU2F3 in this disease. We will now employ two independent
functional approaches to elucidate the critical POU2F3 binding sites/enhancers in the genome of SCLC cells,
which will be leveraged to pinpoint the critical components of the tuft cell lineage circuit that might be targeted
therapeutically. The second Aim will evaluate POU2F3 cofactors, which we have already nominated via an
innovative ChIP-SICAP-mass spectrometry analysis of endogenous POU2F3 binding sites. We will perform
CRISPR exon scanning and biochemical analysis of each cofactor to define the critical POU2F3:cofactor
interactions that selectively support this malignancy. The final Aim of this proposal will employ functional
genomics to devise drug combinations with the IGF1R inhibitor linsitinib that are rational and exploit synthetic-
lethal genetic interactions. We will also employ our latest CRISPR innovation, homolog co-targeting CRISPR
screens, to expose redundant kinase vulnerabilities that are linked with neuroendocrine versus tuft cell variants
of SCLC. In summary, we estimate that the tuft cell-like variant is present in ~18% of SCLC cases, which
corresponds to approximately 5,000 newly diagnosed SCLC cases and approximately 3,500 deaths in the United
States alone each year. Hence, the proposed research could lead to a sustained impact that affects a large
patient population for which novel medicines are desperately needed.

## Key facts

- **NIH application ID:** 10450100
- **Project number:** 5U01CA242919-04
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** CHRISTOPHER VAKOC
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $430,416
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450100

## Citation

> US National Institutes of Health, RePORTER application 10450100, Exploiting POU2F3 addiction in the tuft cell variant of small cell lung cancer (5U01CA242919-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450100. Licensed CC0.

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