The Emergence of Diverse Drug-Resistance Mechanisms from Drug Tolerant Cancer Persister Cells

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dc.contributor.advisorMendell, Joshua T.en
dc.contributor.committeeMemberShay, Jerry W.en
dc.contributor.committeeMemberCobb, Melanie H.en
dc.contributor.committeeMemberAltschuler, Steven J.en
dc.contributor.committeeMemberWu, Lanien
dc.contributor.committeeMemberWu, Jiang I.en
dc.creatorRamirez, Michael Edwarden
dc.creator.orcid0000-0002-8591-1641
dc.date.accessioned2018-01-04T21:09:49Z
dc.date.available2018-01-04T21:09:49Z
dc.date.created2015-12
dc.date.issued2015-08-31
dc.date.submittedDecember 2015
dc.date.updated2018-01-04T21:03:43Z
dc.description.abstractCancer therapy has traditionally focused on eliminating fast-growing populations of cells, yet a growing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a slow-growing "persister" state. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity and clinical relevance of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here, we compared persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We found, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies had acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit--and may even provide a latent reservoir of cells--from which drug-resistance heterogeneity can emerge.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1017760182
dc.identifier.urihttps://hdl.handle.net/2152.5/4448
dc.language.isoenen
dc.subjectAntineoplastic Agentsen
dc.subjectDrug Resistance, Neoplasmen
dc.subjectErlotinib Hydrochlorideen
dc.subjectLung Neoplasmsen
dc.titleThe Emergence of Diverse Drug-Resistance Mechanisms from Drug Tolerant Cancer Persister Cellsen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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