Understanding PI3K/mTOR/MEK signalling in breast cancer. Euphemia Leung Auckland Cancer Society Research Centre University of Auckland
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1 Understanding PI3K/mTOR/MEK signalling in breast cancer Euphemia Leung Auckland Cancer Society Research Centre University of Auckland
2 Receptor status of human breast cancer On a popula>on basis ER+/PR+ (65%) HER2+ (20%) ER- /PR- /HER2- (15%) Triple Nega>ve Cells with different receptor status may respond differently to targeted therapies
3 Agents targeang signaling pathways TrameAnib Growth factors including EGF, Insulin, IGF1 Ras Raf Mek Erk PI3K AKT BEZ235 GSK mtor everolimus Cell growth and survival Baguley and Leung. Breast Cancer, Chapter 11, INTECH, 2011
4 Cell culture models ER+/PR+: MCF- 7 and T47D HER2+ : SKBR3 ER- /PR- /HER2- (TN): MDA- MB- 231 Look at sensi>vity of cell lines to drugs that target signaling pathways
5 Principal quesaons to answer Rela>onship of receptor status to signaling pathways Rela>onship of receptor status to sensi>vity to new targeted agents
6 Receptor status and PI3K/mTOR signaling MCF7 T47D SKBr3 MDA231 IRS PI3K P- AKT S473 AKT P Evl BEZ235 GSK P- p70s6k T389 Tubulin mtor TORC1 p70s6k P rps6 P ER+ ER+ HER2+ TN Cell Growth
7 SensiAvity to PI3K/mTOR inhibitor Everolimus+ BEZ235' GSK * IC50 (nm) 100" 90" 80" 70" 60" 50" 40" 30" 20" 10" 0" * * * 80" 70" 60" 50" 40" 30" 20" 10" 0" * * * 50" 45" 40" 35" 30" 25" 20" 15" 10" 5" 0" * * * ER+ ER+ HER2+ TN ER+ ER+ HER2+ TN ER+ ER+ HER2+ TN MCF/7" T47D" SKBR3" MDA/MB/231" MCF.7" T47D" SKBR3" MDA.MB.231" MCF7" T47D" SKBR3" MDA3MB3231"
8 Receptor status and MAPK signaling RAS RAS Tram P- ERK T202/Y204 MCF7 T47D SKBr3 MDA231 MEK ERK P Total ERK Cell survival ER+ ER+ HER2+ TNBC
9 SensiAvity to MEK inhibitor TrameAnib IC50 (nm) 400" 350" 300" 250" 200" 150" 100" 50" * Trame&nib* * * 0" ER+ ER+ HER2+ TN MCF+7" T47D" SKBR3" MDA+MB+231"
10 Principal quesaons to answer Rela>onship of receptor status to signaling pathways Yes in general Rela>onship of receptor status to sensi>vity to new targeted agents Yes Validate the hypothesis in a larger panel of breast cancer cell lines
11 Expansion to a larger number of cell lines ER+ MCF- 7 tamoxifen resistant sub- lines (5) ER+ MCF- 7 fulvestrant resistant sub- lines (3) ER+ KLP1 TN MCF- 7 fulvestrant resistant sub- lines (3) TN (BaA): BT20, HCC1143, MDA- MB- 468, TN (BaB): MDA- MB- 231, MDA- MB- 436, HBL100
12 CorrelaAon of everolimus and trameanib sensiavity in breast cancer lines mtor inhibitor Everolimus IC50 (nm) MAPK inhibitor Trametinib IC50 (nm) ER+ HER2+ TN ER+ HER2+ TN
13 CorrelaAon of everolimus and trameanib sensiavity in breast cancer lines Receptor status seems to predict ac>vity of signaling pathway However, receptor status does not predict sensi>vity to signaling pathway targeted drugs What s the opposite of Eureka!?
14 Hypothesis When one signaling pathway is blocked, some cells can use an alterna>ve pathway for growth and survival
15 Drug combinaaon Can PI3K/mTOR inhibitor poten>ate MEK inhibitor efficacy in some breast cancer cell lines? RAS RAS PI3K AKT P Trame>nib MEK P ERK Cell survival mtor TORC1 P p70s6k P rps6 Everolimus BEZ235 GSK Cell Growth
16 CombinaAon index antagonism (CI > 1) additive effect (CI = 1) synergism (CI < 1) Chou, Cancer Research Growth inhibition 0% = 0 or 100% = 1
17 CombinaAon effect in MCF7 cells mtor PI3K/mTOR Tra Everolimus BEZ235 GSK Trame>nib CI P.ERK*(T202/Y204)* P.AKT*(S473)* Tubulin* P.70S6K*(T389)* Growth inhibi>on P.S6*(S235/236)* Tubulin*
18 CombinaAon effect in T47D cells mtor PI3K/mTOR Tra Everolimus BEZ235 GSK Trame>nib P.ERK*(T202/Y204)* CI P.AKT*(S473)* Tubulin* P.70S6K*(T389)* Growth inhibi>on P.S6*(S235/236)* Tubulin*
19 CombinaAon effect in SKBR3 cells mtor PI3K/mTOR Tra Everolimus BEZ235 GSK Trame>nib CI P"ERK&(T202/Y204)& P"AKT&(S473)& Tubulin& P"70S6K&(T389)& Growth inhibi>on P"S6&(S235/236)& Tubulin&
20 Summary Signaling seems to be related to receptor status Receptor status does not predict drug sensi>vity in cell lines Sensi>vity of cell growth in culture to kinase inhibitors is likely to be a composite of complex interac>ons involving several signaling pathways. This may have implica>ons for clinical therapy.
21 QuesAon Everolimus: treatment of postmenopausal women with advanced hormone receptor- posi>ve, HER2- nega>ve breast cancer in combina>on with exemestane, aher failure of treatment with letrozole or anastrozole. Should the classifica>on of cell surface receptors influence the choice of drugs that targets these signalling pathways? Intratumor heterogeneity not all tumor cells will have similar drug response
22 Heterogeneity of human breast cancer -Complicate diagnosis -obstruct therapeutic decision making Gx - Good prognosis Gx - Bad prognosis -a biopsy does not provide an adequate reflection of the phenotypic composition of the whole tumour -decisions made based on scoring the dominant phenotype in a given sample might be misleading if they do not account for minor subpopulations with clinically and biologically important distinct features Marusyk et al. 2012, Nature Reviews
23 Biomarker A bad biomarker is as bad as a bad drug Daniel F. Hayes, U of Michigan and IOM committee St Gallen Breast Cancer Conference 2013
24 Acknowledgements Bruce Baguley, Ji- Eun Kim, Marjan Askarian- Amiri, Gordon Rewcastle, Wayne Joseph and everyone from Auckland Cancer Society Research Centre Supported by Breast Cancer Research FoundaAon LoYery Health Grant Genesis Oncology Trust Maurice & Paykel Research Trust Auckland Medical Research FoundaAon Cancer Society Research Grant McClelland Trust Grant
25 Acknowledgements Staying focus in the commo>on..
26 Biomarker
27 Biomarker Seems very straight forward to start with..
28
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