Show simple item record

dc.contributor.advisorBrown, Myles
dc.contributor.advisorGarraway, Levi
dc.contributor.authorLuo, Flora
dc.date.accessioned2019-08-09T09:20:35Z
dash.embargo.terms2019-05-01
dc.date.created2017-05
dc.date.issued2017-05-11
dc.date.submitted2017
dc.identifier.citationLuo, Flora. 2017. Dissecting Response and Resistance to CDK4/6 inhibition in ER+ Breast Cancer. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41142050*
dc.description.abstractHighly specific cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors comprise a novel and exciting class of targeted therapeutics in oncology. CDK4/6 inhibitors, such as palbociclib, abemaciclib and ribociclib prevent cell cycle progression from the first growth phase (G1) to the DNA synthesis (S) phase of the cell cycle. CDK4/6 inhibition in combination with endocrine therapy is the new standard of care for metastatic breast cancers that express the estrogen receptor (ER+). Many preclinical biomarkers of sensitivity to CDK4/6 inhibition, however, are not clinically relevant. Furthermore, some ER+ breast cancer patients present with intrinsic resistance to CDK4/6 inhibitors and others are progressing on therapy. Consequently, effective treatment of metastatic breast cancer patients necessitates an understanding of response and resistance to CDK4/6 inhibition. To this end, we conducted two projects to 1) determine whether breast cancer cells that are dependent on ER signaling require CDK4/6 and 2) identify the landscape of resistance to CDK4/6 inhibition. Recent sequencing studies have revealed that 20% of metastatic breast cancers harbor activating mutations in the gene encoding the ER (ESR1). Furthermore, ER+ breast cancer cells that are resistant to estrogen deprivation therapy exhibit a dependency on CDK4. We found that estrogen-independent growth of ESR1-mutant breast cancer cells require CDK4/6 and that sensitivity to CDK4/6 inhibition is dependent on an intact retinoblastoma protein (RB, the main downstream target of CDK4/6). Thus, ESR1-mutant breast cancer patients may benefit from CDK4/6 inhibition. To systematically identify genes whose upregulation confer resistance to CDK4/6 inhibition, we conducted five near genome-wide open reading frame (ORF) screens. While most in vitro characterizations of resistance have utilized estrogen-rich media, CDK4/6 inhibitors are only approved in combination with endocrine therapy. Thus, to recapitulate the clinical setting more closely, our expression screens utilized two different CDK4/6 inhibitors alone and in combination with estrogen deprivation. Several novel resistance drivers were nominated. In particular, RB phosphorylation emerged as a convergent node of resistance to CDK4/6 inhibition. Together with cultured to resistance cell models and clinical sequencing of patient tumors, our studies identify several strategies to combat resistance and help pinpoint patient populations for CDK4/6 inhibitor treatment.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectCDK4/6 inhibitors
dc.subjectresistance
dc.subjectbreast cancer
dc.titleDissecting Response and Resistance to CDK4/6 inhibition in ER+ Breast Cancer
dc.typeThesis or Dissertation
dash.depositing.authorLuo, Flora
dash.embargo.until2019-05-01
dc.date.available2019-08-09T09:20:35Z
thesis.degree.date2017
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberHahn, William
dc.contributor.committeeMemberBass, Adam
dc.contributor.committeeMemberAplin, Andrew
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dc.identifier.orcid0000-0001-8625-5546
dash.author.emailfluo89@gmail.com


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record