One of the most exciting areas of our research explores the role of programmed cell death, otherwise known as apoptosis, in cancer biology and how to exploit this in the clinic.
So, what is apoptosis and what’s the link to cancer?
Apoptosis is a mechanism of cell death that occurs during normal tissue homeostasis, but also functions to remove damaged cells in a controlled manner1. There are two major players (pro-survival proteins and pro-apoptotic proteins) and the balance of these determines a cell’s fate2.
Pro-survival proteins such as MCL1 are often over-expressed in haematological cancers 3,4. On the one hand, this makes it more challenging to eradicate cancer cells; think of apoptosis as a set of scales – the greater the amount of proteins that favour survival, the harder it is to push a cell into cell death. On the other hand, this over-expression creates a tumour-specific dependence that can be exploited. Indeed, cell death agents are showing promise in haematological cancer5.
Additionally, many targeted therapies and chemotherapies increase the level of pro-apoptotic proteins, ‘priming’ a cell for apoptosis 6. Our goal here is to explore the potential for combining MCL1 inhibitors with other cancer therapies to drive stronger and more durable responses.
Unlocking the full potential of cell death inhibitors
Three recent publications are driving our understanding of how to utilise cell death agents as combination partners, with the potential to inform clinical trial design for MCL1 inhibitors in solid tumours.
As part of a collaboration between Dr Paul Smith (AstraZeneca), Dr Simon Cook from the Babraham Institute and Professor Duncan Jodrell from the CRUK Cambridge Centre, scientists explored the role of apoptosis in response to therapies targeting the BRAF-MEK-ERK pathway, which is often dysregulated in cancer. Although inhibitors of this pathway show promise in BRAF-mutated tumours, response is often short-lived. Research by Dr Matthew Sale shows that while inhibiting the BRAF-MEK-ERK pathway increases the abundance of pro-apoptotic proteins in cells, to fully tip the scales in favour of cell death it is necessary to also inhibit pro-survival proteins. Importantly, understanding the balance of different pro-survival proteins in a tumour is key; melanoma for example is biased towards MCL1 whereas non-small cell lung cancer and colorectal cancer are more dependent on BCLxL for survival. Understanding how the balance of pro-apoptotic proteins influences response to targeted therapies opens new avenues for using cell death agents to drive stronger responses and to overcome resistance to targeted therapies. Read the full publication in Nature Communications.7
Along a similar theme, Dr Rizwan Haq’s lab at Dana-Farber Cancer Institute, in collaboration with scientists at AstraZeneca, investigated mechanisms that may limit the extent to which targeted therapies induce cancer cell death. They found that a range of targeted therapies rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL1. Sequential treatment with targeted therapies and MCL1 inhibitors increased cell death in cell lines and in an animal model of melanoma, suggesting the potential to explore cell death agents as a mechanism to tackle resistance to targeted therapies. Read the full publication in Nature Communications.8
Completing the hat trick, a third research article describes a role for the CUL5 complex in resistance to targeted cancer therapies by degrading pro-apoptotic proteins, which was discovered using flow cytometry-based CRISPR screening. Dr. Shaheen Kabir (UC Berkeley) together with scientists from AstraZeneca describe how targeting components of the CUL5 complex sensitises cancer cells to CDK9 and MCL1 inhibitors, identifying this as an attractive avenue for new target identification and patient biomarker exploration. Read the full publication in eLife9
1) Elmore S, Toxicol Pathol. 2007; 35(4): 495-516
2) Czabotar PE, et al. Nat Rev Mol Cell Biol. 2014;15:49-63.
3) Wuillème-Toumi S, et al. Leukemia. 2005;19(7):1248–1252.
4) Pepper C, et al. Blood. 2008;112(9):3807–3817.
5) Tron AE, et al. Nat. Comm. 2018; 9:5341
6) Wang YF, et al. Clin Cancer Res. 2007;13(16):4934-4942.
7) Targeting melanoma’s MCL1 bias unleashes the potential of BRAF and ERK1/2 pathway inhibitors; Sale MJ, et al. Nat. Comm. 2019.
8) Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies; Montero J, et al. Nat. Comm. 2019
9) The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells; Kabir S et al. eLife doi: 10.7554/elife.44288.
Date of Prep: 14/11/2019
Date of Expiry: 14/11/2019