Scientists identify new therapeutic target in ovarian cancer subtype
with poor prognosis

Date:
September 21, 2021
Source:
The Wistar Institute
Summary:
Mutations in the ARID1A gene are present in more than 50%
of ovarian clear cell carcinomas (OCCC), for which effective
treatments are lacking.

Scientists discovered that loss of ARID1A function enhances a
cellular stress response pathway that promotes survival of cancer
cells, which become sensitive to pharmacological inhibition of
this pathway.



FULL STORY ========================================================================== Mutations in the ARID1A gene are present in more than 50% of ovarian
clear cell carcinomas (OCCC), for which effective treatments are
lacking. Scientists at The Wistar Institute discovered that loss of
ARID1A function enhances a cellular stress response pathway that promotes survival of cancer cells, which become sensitive to pharmacological
inhibition of this pathway. These findings were published online in Cancer Research, a journal of the American Association for Cancer Research,
and point to a new therapeutic opportunity for this type of ovarian
cancer for which new solutions are urgently needed.


========================================================================== Inactivating mutations in the ARID1A tumor suppressor gene are genetic
drivers of OCCC, which does not respond to chemotherapy and carries the
worst prognosis among all subtypes of ovarian cancer.

"The goal of our research is to uncover the molecular changes caused
by ARID1A loss so that we can target them specifically to achieve
effective therapies for this devastating disease," said Rugang Zhang,
Ph.D., deputy director of The Wistar Institute Cancer Center, professor
and leader of the Immunology, Microenvironment & Metastasis Program,
and lead author of the study. "In this study, we focused on a stress
response mechanism that tumors resort to for survival and found a link
that offers a therapeutic opportunity." The endoplasmic reticulum (ER)
is a cellular structure that oversees protein production and harbors
complex mechanisms to respond to the stress caused by accumulation of
misfolded proteins. The ER stress response is frequently hyperactivated
in cancer cells to favor their survival in stressful microenvironment conditions. Therefore, inhibition of this mechanism has been explored
as a therapeutic approach for cancers with hyperactive ER stress response.

The IRE1a/XBP1 pathway is the major signaling pathway involved in the
ER stress response. The protein Inositol-required enzyme alpha (IRE1a)
senses ER stress and activates the transcription factor X-box binding
protein 1 (XBP1), resulting in upregulation of genes that resolve the
ER stress and promote cell survival.

Zhang and colleagues found that ARID1A inhibits the IRE1a/XBP1 pathway
and, consequently, ARID1A loss in ovarian cancer causes an increased
activation of the pathway, creating a dependence of cancer cells on
upregulated IRE1a-XBP1.

Indeed, treatment of ovarian cancer cells that do not express ARID1A
with the selective IRE1? inhibitor B-I09 caused cell death as a result
of unresolved ER stress.

"In some cases, the mechanisms cancer cells exploit to their advantage
also make them vulnerable because they become dependent on certain
pathways," added Zhang. "If we can find ways to block those pathways, we
may be able to use them as weak spots for killing cancer." Importantly,
this observation was confirmed in vivo, as B-I09 treatment reduced tumor
burden and improved survival in mouse models bearing ARID1A-inactivated
ovarian tumors.

Therapeutic resistance enables cancer cells to escape the effects of
single agent treatments, and combination strategies offer a solution for
this major challenge. Therefore, researchers tested the combination of
IRE1a inhibition with histone deacetylase 6 (HDAC6) inhibition, which
is also effective against ARID1A-mutant cancers. Since HDAC6 regulates
the degradation of misfolded proteins, the team hypothesized that the
two treatments may act in synergy to suppress ARID1A-mutant cancers.

"Our findings suggest that pharmacological inhibition of the IRE1a/XBP1
pathway of the ER stress response, alone or in combination with HDAC6 inhibition, represents a potential therapeutic strategy for ARID1A-mutated cancers," said Joseph Zundell, a pre-doctoral trainee in the Zhang lab
and first author on the paper.

========================================================================== Story Source: Materials provided by The_Wistar_Institute. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Joseph A. Zundell, Takeshi Fukumoto, Jianhuang Lin, Nail
Fatkhudinov,
Timothy Nacarelli, Andrew V. Kossenkov, Qin Liu, Joel Cassel,
Chih-Chi Andrew Hu, Shuai Wu, Rugang Zhang. Targeting the IRE1a/XBP1
Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant
Ovarian Cancers.

Cancer Research, 2021; DOI: 10.1158/0008-5472.CAN-21-1545 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210921125103.htm

--- up 2 weeks, 5 days, 8 hours, 25 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)