# Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $166,708

## Abstract

This proposal addresses one of the most urgent needs in the clinical management of head and neck squamous
cell carcinoma (HNSCC), the development of targeted and less toxic therapies. Recent studies have shown that
50-60% of HNSCC tumors harbor mutations in the TP53 tumor suppressor gene with other studies
demonstrating that disruptive mutations in TP53 are associated with worse prognosis and survival. Additional
studies have linked HPV infection as a second pathway to p53 inactivation in HNSCC. Despite overwhelming
evidence implicating p53 functional derangement in the biology and clinical outcome of HNSCC, there are no
targeted therapies that capitalize on this knowledge. Towards this goal, we hypothesized that the driver
oncogenic/tumor suppressor mutations (i.e., TP53 loss) that confer dominant malignant phenotypes in cancer
cells also engender unique, exploitable vulnerabilities. Since p53 mutant HNSCCs are aggressive tumors
incapable of G1 arrest and with higher levels of genomic instability, these tumors rely on a functional G2/M cell
cycle checkpoint to repair the DNA damage that might occur as a result of this instability or through genotoxic
therapy. In support of this hypothesis, we identified p53 synthetic lethal interactions with several G2/M checkpoint
regulators using high throughput arrayed siRNA gene silencing against human kinases in p53-mutated HNSCC.
Moreover, treatment with AZD1775, a specific WEE1 inhibitor, blocked tumor growth as a single agent and
caused tumor regression when used in combination with cisplatin in p53 mutant HNSCC xenografts. To translate
these findings to the clinic, we opened a phase I clinical trial with AZD1775 in combination with neoadjuvant
weekly cisplatin and docetaxel in previously untreated, metastatic HNSCC patients. Building on these successes,
this proposal will provide needed mechanistic understanding on the biology of p53 alterations and G2/M reliance
in HNSCC, while providing translational data to advance WEE1 inhibition with AZD1775 as a novel therapy for
HNSCC. Therefore, in Aim 1 we will determine the mechanism(s) of growth arrest upon WEE1 inhibition in
HNSCC and determine how p53 inactivation affects this response. In Aim 2 we will identify novel sensitizers to
the WEE1 inhibitor AZD1775 to unveil novel synergistic and less toxic partners for combinatorial therapy. Lastly,
in Aim 3, we will leverage our ongoing phase I clinical trial to functionally evaluate the effects of AZD1775 on
tumor biopsies and relevant preclinical models established from patient biopsies before and after treatment to
correlate markers of WEE1 inhibition to p53 status and clinical efficacy for the first time in HNSCC. This new
knowledge will help inform which HNSCC might benefit most from this line of therapy and help advance AZD1775
into phase II clinical trials.

## Key facts

- **NIH application ID:** 10171805
- **Project number:** 5R01CA215647-05
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Bruce E Clurman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $166,708
- **Award type:** 5
- **Project period:** 2017-06-14 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171805

## Citation

> US National Institutes of Health, RePORTER application 10171805, Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer (5R01CA215647-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171805. Licensed CC0.

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