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Cover Page The following handle holds various files of this Leiden University dissertation: http://hdl.handle.net/1887/79947

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Cover Page

The following handle holds various files of this Leiden University dissertation:

http://hdl.handle.net/1887/79947

Author: He, J.

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Uncovering vulnerabilities in

triple-negative breast cancer

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PhD thesis with summary in Dutch

Uncovering vulnerabilities in triple-negative breast cancer

Jichao He @October 2019

The research described in this thesis was performed at the division Drug Discovery

and Safety of Leiden Academic Centre for Drug Research (LACDR), Leiden

University (Leiden, The Netherlands).

The research was financially supported by China Scholarship Council (no.

201407060007) and the European Research Council Advanced grant Triple-BC

(grant no. 322737).

Cover by: Adapted from

www.besthdwallpaper.com/hua-hui/yi-zhu-pu-gong-ying-hua-dt_zh-CN-11102 (under CC0 license) by Jichao He with no intention of

infringing copyright

Thesis lay-out by Jichao He

Printed by Ridderprint | www.ridderprint.nl

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Uncovering vulnerabilities in

triple-negative breast cancer

Proefschrift

Ter verkrijging van de graad van Doctor aan de Universiteit Leiden,

op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker,

volgens besluit van het College voor Promoties

te verdedigen op donderdag 31 oktober 2019

klokke 10:00 uur

door

Jichao He

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Promotor

Prof. Dr. B. van de Water

Co-promotor

Dr. Y. Zhang

Promotiecommissie

Prof. Dr. H. Irth (Chair)

Prof. Dr. J.A. Bouwstra (Secretary)

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Table of Contents

Chapter 1 ... 1

General introduction and scope of the thesis Chapter 2 ... 19

FRET biosensor-based kinase inhibitor screen for ERK and AKT activity reveals differential kinase dependencies for proliferation in TNBC cells Chapter 3 ... 39

A kinome screen for lapatinib drug resistance identifies FYN as a suppressor of EGFR/PI3K/AKT signaling axis dependency in triple-negative breast cancer Chapter 4 ... 57

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer Chapter 5 ... 79

Integrative analysis of genomic amplification-dependent expression and loss-of-function screen identifies ASAP1 as a driver gene in triple-negative breast cancer progression Chapter 6 ... 105

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