TY - JOUR
T1 - EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer
AU - Joseph, Robiya
AU - Dasari, Santosh K.
AU - Umamaheswaran, Sujanitha
AU - Mangala, Lingegowda S.
AU - Bayraktar, Emine
AU - Rodriguez-Aguayo, Cristian
AU - Wu, Yutuan
AU - Nguyen, Nghi
AU - Powell, Reid T.
AU - Sobieski, Mary
AU - Liu, Yuan
AU - Kim, Mark Seungwook
AU - Corvigno, Sara
AU - Foster, Katherine
AU - Hanjra, Pahul
AU - Vu, Thanh Chung
AU - Chowdhury, Mamur A.
AU - Amero, Paola
AU - Stephan, Clifford
AU - Lopez-Berestein, Gabriel
AU - Westin, Shannon N.
AU - Sood, Anil K.
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/1
Y1 - 2024/1
N2 - Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
AB - Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
KW - EphA2
KW - endometrial cancer
KW - histone deacetylase
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U2 - 10.3390/ijms25021278
DO - 10.3390/ijms25021278
M3 - Article
C2 - 38279277
AN - SCOPUS:85183341161
SN - 1661-6596
VL - 25
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 2
M1 - 1278
ER -