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Pharmacologic Inhibition of YAP/TEAD and Development of New Chorioretinal Atrophy
Lindsay K Kozek1, Isaac Bleicher1, Edward Lu1
1Department of Ophthalmology, Mass Eye and Ear, Harvard Medical School, Boston, Massachusetts.
Importance:
As new chemotherapy agents emerge, ophthalmologists may play a role in identifying vision-threatening adverse effects. Inherited retinal degenerations can offer insight into the changes that may result from pharmacologic inhibition of the signaling pathways involved in these conditions.
Objective:
To present a case of a patient treated with a yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD) inhibitor who developed chorioretinal findings that resemble those seen in helicoid peripapillary chorioretinal degeneration (HPCD, also known as Sveinsson chorioretinal atrophy), an autosomal dominant disease caused by loss-of-function variants in TEAD1.
Design, Setting, And Participant:
Case report of a single patient at a large university hospital.
Exposures:
The patient was treated with VT3989, a YAP/TEAD inhibitor, for 5 cycles.
Main Outcomes And Measures:
Clinical evaluation and description of the ocular condition via fundus photography and fundus autofluorescence.
Results:
A woman in her 50s with metastatic mesothelioma diagnosed several years previously presented for evaluation. Nine months before presentation, she had undergone several cycles of treatment with chemotherapy agent VT3989, which inhibits the interaction of the YAP and TEAD proteins that form the terminal transcriptional effector complex of the Hippo pathway, which is involved in control of cell fate, proliferation, apoptosis, and tissue regeneration. She developed visual decline associated with radially oriented areas of retinal pigment epithelium atrophy extending around both optic nerves, along with small scattered atrophic flecks elsewhere. Given the atypical nature of the peripapillary findings and the resemblance to a mild form of HPCD, which is caused by loss-of-function variants in TEAD1, these changes were presumed to be secondary to treatment with the YAP/TEAD inhibitor VT3989.
Conclusions And Relevance:
Downregulation of the Hippo signaling pathway via YAP/TEAD inhibition in an adult patient may result in a phenotype resembling a mild form of HPCD (Sveinsson chorioretinal atrophy), underscoring the importance of this pathway in maintenance of the adult retina and retinal pigment epithelium. As novel cancer therapeutics continue to emerge, it may be important to ensure ophthalmologic monitoring of patients on drugs targeting the Hippo pathway.
Insights
Chemotherapy targeting the Hippo pathway with a yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD) inhibitor caused vision-threatening chorioretinal changes. This highlights the Hippo pathway
Area of Science:
- Ophthalmology and Oncology
- Molecular Biology and Genetics
- Retinal Degeneration Research
Background:
- Emerging chemotherapy agents necessitate ophthalmologic monitoring for vision-threatening adverse effects.
- Inherited retinal degenerations provide models for understanding pharmacologic inhibition of signaling pathways.
- The Hippo signaling pathway, involving YAP/TEAD, regulates cell fate and tissue regeneration.
Purpose of the Study:
- To report a case of chorioretinal findings in a patient treated with a YAP/TEAD inhibitor.
- To compare these findings to helicoid peripapillary chorioretinal degeneration (HPCD).
Main Methods:
- A case report of a single patient treated with the YAP/TEAD inhibitor VT3989.
- Clinical evaluation including fundus photography and fundus autofluorescence.
- Analysis of ocular changes in relation to chemotherapy exposure.
Main Results:
- A patient receiving VT3989 developed visual decline and retinal pigment epithelium atrophy around the optic nerves.
- Ocular findings resembled a mild form of HPCD (Sveinsson chorioretinal atrophy).
- These changes were presumed secondary to YAP/TEAD inhibition by VT3989.
Conclusions:
- Hippo pathway downregulation via YAP/TEAD inhibition can induce a phenotype similar to mild HPCD in adults.
- This underscores the Hippo pathway's critical role in maintaining retinal health.
- Ophthalmologic monitoring is crucial for patients receiving novel Hippo pathway-targeting cancer therapeutics.
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