fassl, anne, lachowicz, iga, butter, deborah, Brain, Christopher, Sheng, Qing, Loo, Alice, michowski, wojciech, otto, tobias, abu-remaileh, monther, stepien, piotr, bergholtz, johann, jovanovic, bojana, nowak, karolina, erikson, maria, zhao, jean, sabatini, david, jeselson, rinath, brown, myles, polyak, kornelia and sicinski, piotr (2020) Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Science advances, 6 (25). ISSN 2375-2548

Abstract

Breast cancer is the most common type of cancer in women and the second leading cause of cancer death among women. While significant progress has been made in the treatment of hormone receptor (HR) positive, HER2 negative and HER2-amplified breast cancer in the last decades, Triple negative breast cancer (TNBC) is lacking behind. Still today, chemotherapy is the only treatment option, but response rates are low and only a small fraction of patients can successfully be treated. Here we show, that CDK4/6 inhibitors which are FDA-approved for the treatment of HR+/HER2negative breast cancer and significantly improved treatment outcome in this type of breast cancer, also represent a promising therapy option for TNBC in contrast to the current view. We show, that a subset of TNBCs despite being resistant to chemical inhibition of CDK4/6 strictly depend on CDK4/6 kinases for proliferation. We identified lysosomal sequestration of the drug and therefore limited bioavailability at its target site responsible for the discrepancy. We show that increased number of lysosomes correlates with resistance and inhibition of the lysosome renders these cells fully sensitive to CDK4/6 inhibitors. We provide strategies how to overcome resistance by means of FDA-approved lysosomotropic agents that raise lysosomal pH, co-inhibition of CDK2 or the use of structurally altered CDK4/6 inhibitors with decreased basic characteristics. We also provide a biomarker to stratify patients for successful CDK4/6 inhibitor therapy. Moreover, we show that this mechanism of resistance also underlies cases of acquired resistance in HR+/HER2negative breast cancer and importantly we provide evidence that increased lysosomal sequestration operates in patients presenting resistant to treatment with the CDK4/6 inhibitor palbociclib. Our study therefore suggests that CDK4/6 inhibitor therapy could be a treatment option for a subset of TNBCs where new targeted therapeutic intervention is so urgently needed and furthermore, offers strategies how to overcome resistance in HR+/HER2-negative breast cancer where CDK4/6 inhibition is already successfully applied. In summary, our study provides ways on how to improve therapeutic use of this promising new class of anti-cancer agents.

Item Type:	Article
Date Deposited:	08 Sep 2020 00:45
Last Modified:	08 Sep 2020 00:45
URI:	https://oak.novartis.com/id/eprint/40441