# Role of necroptosis in colorectal cancer therapy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $436,808

## Abstract

PROJECT SUMMARY/ABSTRACT
This application is responsive to PA-17-440: The Interplay of Cell Death Pathways in Cancer Cell Survival and
Resistance to Therapy (R01). Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the US.
Most CRC patients are not responsive to therapeutic treatment. Induction of programmed cell death, widely
known as apoptosis, is a key effect of anticancer therapy. Recent studies indicate that programmed cell death is
not confined to caspase-dependent apoptosis, but includes necroptosis, a regulated form of necrotic death
controlled by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like protein
(MLKL). Accumulating evidence suggests that necroptosis functions as a defensive mechanism against
oncogenic mutations and pathogens, and can be utilized by a variety of anticancer agents to kill cancer cells.
However, the regulatory mechanisms and functional role of necroptosis in anticancer therapy are poorly
understood. Despite extensive efforts for restoring apoptosis in cancer cells, few attempts have been made to
manipulate necroptosis for improving anticancer therapy, largely due to insufficient understanding of this newly
defined cell death modality. Our preliminary data show that frequent loss of RIP3 expression in CRCs is
associated with poor clinical outcomes. Necroptosis can be engaged by common chemotherapeutics such as
5-fluorouracil (5-FU) to kill a subset of CRC cells with RIP3 expression, and is associated with a robust antitumor
immune response. We also identified a novel necroptosis pathway involving the BH3-only Bcl-2 family protein
PUMA, which activates RIP3 and MLKL to initiate necroptosis in response to anticancer agents. Based on these
findings, we propose to test the hypothesis that PUMA/RIP3-mediated necroptosis plays a critical role in
determining therapeutic response in a subset of CRC cells via both cell intrinsic and immunologic effects, which
can be targeted to improve CRC therapy. Aim 1: Define the context and mechanism of necroptosis induction in
CRC cells by anticancer agents; Aim 2: Delineate the functional role of necroptosis in the killing of CRC cells by
anticancer agents; and Aim 3: Determine if manipulating necroptosis can be used to overcome therapeutic
resistance of CRCs. The proposed studies will provide new mechanistic insights on necroptosis induction by
anticancer agents in CRC cells. They will clarify how the interplay of apoptosis and necroptosis mediates
response to anticancer therapy, and provide proof-of-principle evidence for stimulating necroptosis to enhance
tumor cell killing and antitumor immune response for improving CRC treatment.

## Key facts

- **NIH application ID:** 10410392
- **Project number:** 5R01CA236271-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Lin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $436,808
- **Award type:** 5
- **Project period:** 2019-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410392

## Citation

> US National Institutes of Health, RePORTER application 10410392, Role of necroptosis in colorectal cancer therapy (5R01CA236271-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10410392. Licensed CC0.

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