The role of Bcl-2 proteins in regulating metabolism in normal and tumour cells
Lead Research Organisation:
Babraham Institute
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Tumour cells exhibit a number of properties that set them apart from normal cells. Understanding what makes a tumour cell different from a normal cell is important as it may allow us to identify new ways to selectively kill tumour cells. Tumour cells differ markedly from normal cells in the way they generate energy, being far more dependent upon the metabolism of glucose (a process known as glycolysis) than normal cells. We are interested in determining if this is an ‘Achilles heel’ by which we can attack tumour cells. If we disrupt glycolysis do tumour cells die? If so, how do they die? If not then, are they now more vulnerable to death in response to other drugs?
Planned Impact
unavailable
People |
ORCID iD |
| Simon Cook (Principal Investigator) |
Publications
Caunt CJ
(2015)
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road.
in Nature reviews. Cancer
Darling NJ
(2014)
The role of MAPK signalling pathways in the response to endoplasmic reticulum stress.
in Biochimica et biophysica acta
Paterson A
(2012)
Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia.
in Blood
Saez-Rodriguez J
(2015)
Modeling Signaling Networks to Advance New Cancer Therapies.
in Annual review of biomedical engineering
Sale MJ
(2014)
The increase in BIK expression following ERK1/2 pathway inhibition is a consequence of G1 cell-cycle arrest and not a direct effect on BIK protein stability.
in The Biochemical journal
Sale MJ
(2013)
That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance.
in British journal of pharmacology
| Description | We have demonstrated links between the abundance of NAD+, a critical cofactor in hundreds of metabolic reactions, and the BCL2 protein family. Specifically reduction in the abundance of NAD+ (which os observed durign ageing) results in the activation of BCL2 celld eath pathway. |
| Exploitation Route | We are currently exploring links between NAD+ abundance, autophagy and cell death pathways. This may be relevant to normal ageing but also to certian diseases that are more prevalent as we age. We will explore this through discussiosn with the Biotech/Pharma sector |
| Sectors | Education Healthcare Pharmaceuticals and Medical Biotechnology |
| Description | Impacts form this work are still emerging but we anticipate the results will be of interest to the Pharma sector and may provide new insights for treating disease |
| Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Title | BIM KO, BMF KO and BIM/BMF DKO CRISPR cell lines - A375 cells |
| Description | A375 lines with deletions of BIM, BMF or both BIM and BMF generated by CRISPR/Cas9 and validated |
| Type Of Material | Cell line |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | These cell lines have been used to define the mechanism of action of a novel drug combination that effectively kills melanoma cells Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Sale MJ, Minihane E, Monks NR, Gilley R, Richards FM, Schifferli KP, Andersen CL, Davies EJ, Vicente MA, Ozono E, Markovets A, Dry JR, Drew L, Flemington V, Proia T, Jodrell DI, Smith PD, Cook SJ. Nat Commun. 2019 Nov 14;10(1):5167. doi: 10.1038/s41467-019-12409-w |
| URL | https://pubmed.ncbi.nlm.nih.gov/31727888/ |
| Title | BIM KO, BMF KO and BIM/BMF DKO CRISPR cell lines - SW620 cells |
| Description | SW620 cell lines with deletions of BIM, BMF or both BIM and BMF generated by CRISPR/Cas9 and validated |
| Type Of Material | Cell line |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | These cells have been used to define the mechanism of action of a novel drug combination that effectively kills colorectal cancer cells |
| Title | BIM/BMF DKO CRISPR cell lines - SK-MEL-30 |
| Description | SK-MEL-30 lines with deletions of both BIM and BMF generated by CRISPR/Cas9 and validated |
| Type Of Material | Cell line |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | These cell lines have been used to define the mechanism of action of a novel drug combination that effectively kills melanoma cells Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Sale MJ, Minihane E, Monks NR, Gilley R, Richards FM, Schifferli KP, Andersen CL, Davies EJ, Vicente MA, Ozono E, Markovets A, Dry JR, Drew L, Flemington V, Proia T, Jodrell DI, Smith PD, Cook SJ. Nat Commun. 2019 Nov 14;10(1):5167. doi: 10.1038/s41467-019-12409-w |
| URL | https://pubmed.ncbi.nlm.nih.gov/31727888/ |
| Title | Mammalian expression plasmids for BIM mutants |
| Description | Mammalian expression plasmids encoding a variety of splice variants and mutants of the pro-apoptotic protein BIM, including phospho-site mutants |
| Type Of Material | Technology assay or reagent |
| Provided To Others? | Yes |
| Impact | New insights into the post-translational regulation of the pro-apoptptic protein BIM. |
| Description | AMPK signalling |
| Organisation | Imperial College London |
| Department | Institute of Clinical Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have been investigating the role of the AMPK kinase in detecting changes in cellular NAD+ levels |
| Collaborator Contribution | Provision of a small molecule agonist of AMPK |
| Impact | None yet but a manuscript is in preparation |
| Start Year | 2015 |
| Description | AstraZeneca ERK |
| Organisation | AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | We want to understand the various mechanisms by which ERK1/2 pathway-addicted tumour cells adapt and acquire resistance to the MEK1/2 inhibtor Selumetinib. We have generated a variety of human tumour cell lines with acquired resistance to the clinical candidate MEK1/2 inhibitor Selumetinib. These include cell lines in which BRAF is the driving oncogene but also those in which KRAS is the driving oncogene. We have analysed the activation state of the ERK1/2 pathway in these cells and in some cases validated the resistance mechanism. In other cases this analysis is ongoing. In some models we find that resistance is reversible upon drug withdrawal suggesting that resistant cells actually have a fitness deficit in the absence of drug. We are investigating the mechanisms that underlie this fitness deficit. For our partner (AstraZeneca/CRUK) this may allow development of rational strategies to overcome or delay resistance and thereby provide more durable drug responses. For our own basic biological interests this should provide insights into how this key cell fate signalling pathway is regulated; this may be relevant to emerging regenerative medicine protocols. |
| Collaborator Contribution | AstraZeneca have performed a variety of Next Gen Seq analyses on samples provided by us to identify genetic and transcriptomic changes associated with resistance; these may be candidate resistance drivers. They are also performing xenograft studies to test specific hypotheses that emerge form our studies. Our collaborators at the University of Bath are investigating how the magnitude of ERK1/2 signalling can impart different tumour cell responses when Selumetinib is withdrawn from resistant cells. In a three-way collaboration between our lab, the CRUK-CI and AstraZeneca we are peforming high throughput drug combination screens to identify drugs that combine with Selumetinib to provide superior tumour growth inhibition or tumour cell death. |
| Impact | Much of this is still early stage. However, high throughput drug screening has identified several drug combinations that markedly transform the growth inhibitory effects of Selumetinib. Our analysis of new resistance models has identified several completely novel potential mechanisms which we are in the process of validating. These studies will lead to further papers in addition those publications already reported and may contribute to the testing of new drug combinations in the clinic in the future. |
| Start Year | 2013 |
| Description | AstraZeneca ERK |
| Organisation | Cancer Research UK Cambridge Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We want to understand the various mechanisms by which ERK1/2 pathway-addicted tumour cells adapt and acquire resistance to the MEK1/2 inhibtor Selumetinib. We have generated a variety of human tumour cell lines with acquired resistance to the clinical candidate MEK1/2 inhibitor Selumetinib. These include cell lines in which BRAF is the driving oncogene but also those in which KRAS is the driving oncogene. We have analysed the activation state of the ERK1/2 pathway in these cells and in some cases validated the resistance mechanism. In other cases this analysis is ongoing. In some models we find that resistance is reversible upon drug withdrawal suggesting that resistant cells actually have a fitness deficit in the absence of drug. We are investigating the mechanisms that underlie this fitness deficit. For our partner (AstraZeneca/CRUK) this may allow development of rational strategies to overcome or delay resistance and thereby provide more durable drug responses. For our own basic biological interests this should provide insights into how this key cell fate signalling pathway is regulated; this may be relevant to emerging regenerative medicine protocols. |
| Collaborator Contribution | AstraZeneca have performed a variety of Next Gen Seq analyses on samples provided by us to identify genetic and transcriptomic changes associated with resistance; these may be candidate resistance drivers. They are also performing xenograft studies to test specific hypotheses that emerge form our studies. Our collaborators at the University of Bath are investigating how the magnitude of ERK1/2 signalling can impart different tumour cell responses when Selumetinib is withdrawn from resistant cells. In a three-way collaboration between our lab, the CRUK-CI and AstraZeneca we are peforming high throughput drug combination screens to identify drugs that combine with Selumetinib to provide superior tumour growth inhibition or tumour cell death. |
| Impact | Much of this is still early stage. However, high throughput drug screening has identified several drug combinations that markedly transform the growth inhibitory effects of Selumetinib. Our analysis of new resistance models has identified several completely novel potential mechanisms which we are in the process of validating. These studies will lead to further papers in addition those publications already reported and may contribute to the testing of new drug combinations in the clinic in the future. |
| Start Year | 2013 |
| Description | AstraZeneca ERK |
| Organisation | University of Bath |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We want to understand the various mechanisms by which ERK1/2 pathway-addicted tumour cells adapt and acquire resistance to the MEK1/2 inhibtor Selumetinib. We have generated a variety of human tumour cell lines with acquired resistance to the clinical candidate MEK1/2 inhibitor Selumetinib. These include cell lines in which BRAF is the driving oncogene but also those in which KRAS is the driving oncogene. We have analysed the activation state of the ERK1/2 pathway in these cells and in some cases validated the resistance mechanism. In other cases this analysis is ongoing. In some models we find that resistance is reversible upon drug withdrawal suggesting that resistant cells actually have a fitness deficit in the absence of drug. We are investigating the mechanisms that underlie this fitness deficit. For our partner (AstraZeneca/CRUK) this may allow development of rational strategies to overcome or delay resistance and thereby provide more durable drug responses. For our own basic biological interests this should provide insights into how this key cell fate signalling pathway is regulated; this may be relevant to emerging regenerative medicine protocols. |
| Collaborator Contribution | AstraZeneca have performed a variety of Next Gen Seq analyses on samples provided by us to identify genetic and transcriptomic changes associated with resistance; these may be candidate resistance drivers. They are also performing xenograft studies to test specific hypotheses that emerge form our studies. Our collaborators at the University of Bath are investigating how the magnitude of ERK1/2 signalling can impart different tumour cell responses when Selumetinib is withdrawn from resistant cells. In a three-way collaboration between our lab, the CRUK-CI and AstraZeneca we are peforming high throughput drug combination screens to identify drugs that combine with Selumetinib to provide superior tumour growth inhibition or tumour cell death. |
| Impact | Much of this is still early stage. However, high throughput drug screening has identified several drug combinations that markedly transform the growth inhibitory effects of Selumetinib. Our analysis of new resistance models has identified several completely novel potential mechanisms which we are in the process of validating. These studies will lead to further papers in addition those publications already reported and may contribute to the testing of new drug combinations in the clinic in the future. |
| Start Year | 2013 |
| Description | Lecture in Cancer Biology and Medicine training course |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Postgraduate students |
| Results and Impact | I presented a lecture on how signalling pathways are remodelled to drive innate or acquired resistance to new targeted anti-cancer agents that are clincially approved or in development. The lecturer reached approx 60 Master and PhD students, clinicians some patient advocates and charity-funded researchers. There was a vibrant follow-up Q&A session and new contacts were established with the prospect of future collaborations. In feedback >80% of the audience found it useful |
| Year(s) Of Engagement Activity | 2020,2021 |
| Description | Science Open Day |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | Students visited the lab and undertook small lab-based proejcts supervised by students/post-docs and myself. I explained the research that we do and discussed ethical issues such as the use of animals in research. This precipitated excellent discussion and dialogue. We received excellent feedback from the schools involved and requests for further outreach activities |
| Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017,2018,2019,2020 |