TY - JOUR
T1 - Combination of EphA2- and Wee1-Targeted Therapies in Endometrial Cancer
AU - Dasari, Santosh K.
AU - Joseph, Robiya
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 - Chowdhury, Mamur A.
AU - Amero, Paola
AU - Stephan, Clifford
AU - Lopez-Berestein, Gabriel
AU - Westin, Shannon N.
AU - Sood, Anil K.
N1 - Funding Information:
This work is supported, in part, by NIH grants CA098258, R35CA209904, the American Cancer Society Research Professor Award, the Frank McGraw Memorial Chair in Cancer Research, the Dunwoody Fund, the Gordon Fund, and NIH-NCI grant U01 CA213759. C.S. is supported by the CPRIT-funded Combinatorial Drug Discovery Program (RP200668 and RP150578).
Funding Information:
This work was supported by the National Institutes of Health/National Cancer Institute under award number P30CA016672. We thank Madison Semro and Sunita Patterson (Scientific Publications, Research Medical Library, MD Anderson Cancer Center) for editorial work.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination’s effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development.
AB - EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination’s effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development.
KW - endometrial cancer
KW - EphA2
KW - Wee1
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U2 - 10.3390/ijms24043915
DO - 10.3390/ijms24043915
M3 - Article
C2 - 36835335
AN - SCOPUS:85149042354
SN - 1661-6596
VL - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 3915
ER -