# Replication Stress Sensing and Signaling Defects in SCLC

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $350,490

## Abstract

PROJECT SUMMARY
 The underlying mechanisms that account for initial sensitivity to of SCLC to chemotherapy followed by
profound therapeutic resistance are just beginning to be elucidated. These mechanisms appear to converge on
the ways in which SCLC copes with the replication stress and DNA damage induced by chemotherapy-induced
lesions on DNA. One such mechanism is the epigenetic silencing of SLFN11, a gene implicated as a broad-
spectrum sensitizer to replication stress and DNA damage. Interestingly, mutations in hallmark DNA damage
response and repair genes are infrequent in SCLC which instead appears to be sensitized to chemotherapy by
SLFN11 expression. The precise cellular responses to replication stress altered by SLFN11 expression are not
well-understood and are remarkably understudied, despite SLFN11 expression having been more strongly
associated with chemotherapy sensitivity than mutations in DNA repair genes pan-cancer.
 This study proposes three Specific Aims. Specific Aim 1 focuses on clarifying the functional
requirements of SLFN11 on the early stages of the replication stress response. To do this, we will express
mutant SLFN11 proteins in cell lines. With these cell lines in hand, we will be able to separate the chronic
effects of SLFN11 expression, which may include altering the steady state levels of many proteins in the cell,
from the acute effects that have been reported to occur at stalled replications forks. In a complementary series
of experiments, Specific Aim 2 will focus on specific downstream signaling cascades impinged upon by
SLFN11. Specific Aim 3 will specifically interrogate downstream targets of SLFN11 to assess their suitability
as candidate drug targets in cell line and animal models of SCLC. These experiments will be important to
determine whether it is possible to develop new strategies to sensitize SCLC to existing therapies that work
through DNA damage.
 These Specific Aims will resolve long-standing questions in the field vis-à-vis to what extent the
translation inhibition or fork poisoning effects of SLFN11 are important in sensitization to replication stress.
They will also make it possible to benchmark new therapeutic strategies for their ability to mimic SLFN11
expression and chemosensitize SCLC that lose SLFN11 expression. Together, these studies will significantly
enhance our understanding of SLFN11 as a candidate biomarker of response while also enabling the
development of new therapeutic strategies to restore and sustain its expression in SCLC.

## Key facts

- **NIH application ID:** 10848845
- **Project number:** 1P01CA288368-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** John Thomas Poirier
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $350,490
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848845

## Citation

> US National Institutes of Health, RePORTER application 10848845, Replication Stress Sensing and Signaling Defects in SCLC (1P01CA288368-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848845. Licensed CC0.

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