Targeting WEE1 Inhibits Growth of Breast Cancer Cells That Are Resistant to Endocrine Therapy and CDK4/6 Inhibitors

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dc.contributor.authorFallah, Yassien
dc.contributor.authorDemas, Diane M.en
dc.contributor.authorJin, Luen
dc.contributor.authorHe, Weien
dc.contributor.authorShajahan-Haq, Ayesha N.en
dc.date.accessioned2022-04-14T16:57:29Zen
dc.date.available2022-04-14T16:57:29Zen
dc.date.issued2021-07-01en
dc.description.abstractDespite the success of antiestrogens in extending overall survival of patients with estrogen receptor positive (ER+) breast tumors, resistance to these therapies is prevalent. ER+ tumors that progress on antiestrogens are treated with antiestrogens and CDK4/6 inhibitors. However, 20% of these tumors never respond to CDK4/6 inhibitors due to intrinsic resistance. Here, we used endocrine sensitive ER+ MCF7 and T47D breast cancer cells to generate long-term estrogen deprived (LTED) endocrine resistant cells that are intrinsically resistant to CDK4/6 inhibitors. Since treatment with antiestrogens arrests cells in the G1 phase of the cell cycle, we hypothesized that a defective G1 checkpoint allows resistant cells to escape this arrest but increases their dependency on G2 checkpoint for DNA repair and growth, and hence, targeting the G2 checkpoint will induce cell death. Indeed, inhibition of WEE1, a crucial G2 checkpoint regulator, with AZD1775 (Adavosertib), significantly decreased cell proliferation and increased G2/M arrest, apoptosis and gamma-H2AX levels (a marker for DNA double stranded breaks) in resistant cells compared with sensitive cells. Thus, targeting WEE1 is a promising anti-cancer therapeutic strategy in standard therapy resistant ER+ breast cancer.en
dc.description.notesThis research was partly funded by Public Health Service grant R01-CA201092 to ASH. YF was supported by a Susan G Komen TREND grant (GTDR15330383). Technical services were provided by the following shared resources at Georgetown University Medical Center: Tissue Culture and Flow Cytometry Shared Resources that were funded through Public Health Service award 1P30-CA-51008 (Lombardi Comprehensive Cancer Center Support Grant).en
dc.description.sponsorshipPublic Health ServiceUnited States Department of Health & Human ServicesUnited States Public Health Service [R01-CA201092, 1P30-CA-51008]; Susan G Komen TREND grant [GTDR15330383]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fonc.2021.681530en
dc.identifier.issn2234-943Xen
dc.identifier.other681530en
dc.identifier.pmid34277427en
dc.identifier.urihttp://hdl.handle.net/10919/109666en
dc.identifier.volume11en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectestrogen receptor positive breast canceren
dc.subjectendocrine therapyen
dc.subjectdrug resistanceen
dc.subjectCDK4en
dc.subject6 inhibitorsen
dc.subjectribocicliben
dc.subjectWEE1en
dc.subjectAZD1775en
dc.titleTargeting WEE1 Inhibits Growth of Breast Cancer Cells That Are Resistant to Endocrine Therapy and CDK4/6 Inhibitorsen
dc.title.serialFrontiers in Oncologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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