| LDR | | 00000nam u2200205 4500 |
| 001 | | 000000433240 |
| 005 | | 20200225115301 |
| 008 | | 200131s2019 ||||||||||||||||| ||eng d |
| 020 | |
▼a 9781085559638 |
| 035 | |
▼a (MiAaPQ)AAI13857211 |
| 040 | |
▼a MiAaPQ
▼c MiAaPQ
▼d 247004 |
| 082 | 0 |
▼a 574 |
| 100 | 1 |
▼a Kharbanda, Akriti. |
| 245 | 14 |
▼a The Regulation of EGFR Signaling and KRAS Tumorigenesis by Receptor Palmitoylation. |
| 260 | |
▼a [S.l.]:
▼b University of Pennsylvania.,
▼c 2019. |
| 260 | 1 |
▼a Ann Arbor:
▼b ProQuest Dissertations & Theses,
▼c 2019. |
| 300 | |
▼a 196 p. |
| 500 | |
▼a Source: Dissertations Abstracts International, Volume: 81-02, Section: B. |
| 500 | |
▼a Advisor: Witze, Eric . |
| 502 | 1 |
▼a Thesis (Ph.D.)--University of Pennsylvania, 2019. |
| 506 | |
▼a This item must not be sold to any third party vendors. |
| 506 | |
▼a This item must not be added to any third party search indexes. |
| 520 | |
▼a Non-Small Cell Lung Cancer (NSCLC) is often characterized by mutually exclusive mutations in epidermal growth factor receptor (EGFR) or KRAS. The mutual exclusivity of these mutations is due to synthetic lethality, revealing a potential therapeutic vulnerability if possible to selectively activate EGFR in KRAS mutant cells. This thesis work demonstrates a previously unidentified mechanism of EGFR signal regulation through palmitoylation, the addition of the 16-carbon palmitate. The palmitoyltransferase, DHHC20, catalyzes this palmitoylation to Cys1025, Cys1122 and Cys1034 on the C-terminal tail of EGFR. Loss of EGFR palmitoylation leads to hyperactivation of the receptor, but decreased cell growth of KRAS mutant cancer cells. While KRAS is still an elusive therapeutic target, here we report that disrupting EGFR palmitoylation by ablation of DHHC20 or expression of a palmitoylation-resistant EGFR mutant blocks tumorigenesis in a KRAS-driven mouse model of lung adenocarcinoma. Mechanistically, we show that in the presence of oncogenic KRAS, unpalmitoylated, active EGFR increases signaling through the MAP Kinase pathway while simultaneously reducing PI3K/AKT signaling leading to a severe decrease in expression of the central proliferation-associated transcription factor, Myc, similarly as impossible to therapeutically target as KRAS. We find that the dysregulation of EGFR palmitoylation from DHHC20 loss disrupts the delicate balance of MAPK and PI3K signaling leading to detrimental loss of Myc expression and subsequent loss of cell growth. Initially, we discovered that inhibiting EGFR palmitoylation increases sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib, in cell lines specifically harboring mutant KRAS and interestingly, in cells harboring the drug-resistant EGFR gatekeeper mutation through a mechanism that is still unclear. We have now determined that inhibition of DHHC20 induces sensitivity of KRAS mutant cells to a clinically available pan-PI3K inhibitor, Buparlisib, more effective than gefitinib in inducing cell death by directly blocking the residual, necessary PI3K signaling. Thus, this previously unappreciated mechanism of receptor signaling modulation driven by the palmitoyltransferase, DHHC20, can be exploited to treat the currently incurable mutant KRAS NSCLCs. |
| 590 | |
▼a School code: 0175. |
| 650 | 4 |
▼a Cellular biology. |
| 650 | 4 |
▼a Molecular biology. |
| 650 | 4 |
▼a Biochemistry. |
| 690 | |
▼a 0379 |
| 690 | |
▼a 0307 |
| 690 | |
▼a 0487 |
| 710 | 20 |
▼a University of Pennsylvania.
▼b Cell and Molecular Biology. |
| 773 | 0 |
▼t Dissertations Abstracts International
▼g 81-02B. |
| 773 | |
▼t Dissertation Abstract International |
| 790 | |
▼a 0175 |
| 791 | |
▼a Ph.D. |
| 792 | |
▼a 2019 |
| 793 | |
▼a English |
| 856 | 40 |
▼u http://www.riss.kr/pdu/ddodLink.do?id=T15490834
▼n KERIS
▼z 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
| 980 | |
▼a 202002
▼f 2020 |
| 990 | |
▼a ***1816162 |
| 991 | |
▼a E-BOOK |