dc.contributor.advisor | Brown, Myles | |
dc.contributor.advisor | Garraway, Levi | |
dc.contributor.author | Luo, Flora | |
dc.date.accessioned | 2019-08-09T09:20:35Z | |
dash.embargo.terms | 2019-05-01 | |
dc.date.created | 2017-05 | |
dc.date.issued | 2017-05-11 | |
dc.date.submitted | 2017 | |
dc.identifier.citation | Luo, 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.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:41142050 | * |
dc.description.abstract | Highly 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.sponsorship | Medical Sciences | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dash.license | LAA | |
dc.subject | CDK4/6 inhibitors | |
dc.subject | resistance | |
dc.subject | breast cancer | |
dc.title | Dissecting Response and Resistance to CDK4/6 inhibition in ER+ Breast Cancer | |
dc.type | Thesis or Dissertation | |
dash.depositing.author | Luo, Flora | |
dash.embargo.until | 2019-05-01 | |
dc.date.available | 2019-08-09T09:20:35Z | |
thesis.degree.date | 2017 | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.level | Doctoral | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Doctor of Philosophy | |
thesis.degree.name | Doctor of Philosophy | |
dc.contributor.committeeMember | Hahn, William | |
dc.contributor.committeeMember | Bass, Adam | |
dc.contributor.committeeMember | Aplin, Andrew | |
dc.type.material | text | |
thesis.degree.department | Medical Sciences | |
thesis.degree.department | Medical Sciences | |
dash.identifier.vireo | | |
dc.identifier.orcid | 0000-0001-8625-5546 | |
dash.author.email | fluo89@gmail.com | |