Cancer kinomics: Kinome-wide analysis of drug-resistance mechanisms in human cancers
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Integrative Biology
Abstract
Summary:
The North West suffers disproportionately from cancer-associated morbity. We will explore mechanisms that enable cancer cells obtained from human patient samples to survive prolonged exposure to protein kinase inhibitors, key clinical weapons for personalized cancer therapy. This is a strategic Industry:Academic PhD partnership that was ""pump-primed"" by a 2016 University of Liverpool MRC Proximity to Discovery Award, which allowed us to generate important preliminary findings. These data confirm that cell populations that generate drug-resistance in patients treated with kinase inhibitors exhibit unique genetic profiles distinct from those in acutely-dosed patients, and their identification provides an exciting new opportunity for targetting mechanisms of drug-resistance in cancer patients.
Background:
Prolonged treatment of cancer cells with kinase inhibitors leads to transcriptional 're-wiring' of kinase signalling networks. This pathway 'evolution' can be analysed by nanoString-based mRNA kinome profiling and proteomics, quantitative technologies we are developing in Liverpool for personalized cancer cell profiling. Through a recent collaboration with the MRC-PPUU (University of Dundee), we have established that under acute and prolonged conditions of kinase inhibitor exposure, different protein kinase mRNAs are upregulated, and that one can substitute for drug-inhibited pathways (Bago et al., 2016, EMBO J. 35, 9802). This finding has significant consequences for deciding how, and when, combinations of therapeutics should be given to stratified patients. What is missing is understanding of the mRNA and proteomic kinase signatures found in patient-specific cancers, and its prognostic or diagnostic potential in oncology. This MRC DiMeN PhD studentship supports an established collaborative network, and includes skill-set training outside the academic environment with AstraZeneca. This successful pharmaceutical team contributed to the development of Tagrisso/Omisertinib for metastatic non-small cell lung cancer, the fastest protein kinase inhibitor to receive approval in terms of passage from trials to its regulatory approval in 2016.
Studentship work package:
We will evaluate response and resistance 'signatures' found in clinically-relevant cancer cell panels challenged with clinical kinase inhibitors. These patient-derived cells are part of a unique AstraZeneca panel. Data produced from our Industry and academic partnership will inform how whole-kinome analysis can be used to individual patients' advantage. Specifically, it has the potential to increase the therapeutic potential of targeting drug-resistant persistors in various human cancers.
Overall PhD studentship outcomes could include:
1) Provide PhD student(s) with collaborative research training in academic and non-academic settings of stratified medicine excellence but with different technological strengths. To include ~3 months placement at AZ to maximize generic and transferable skills.
2) Strengthen collaborations between DiMeN Universities and help position Liverpool as a training centre of excellence for kinome-based screening of drug-treated tumour samples.
3) Whole kinome expression data for clinical compounds in ~50 patient-derived cancer cell lines of known genomic and drug-responsiveness.
4) Whole kinome dynamics, and selected phosphoproteomics for clinical compounds after i) acute and ii) prolonged compound exposure at a concentration where target engagement is known.
5) Screening of AZ and commercial drug libraries for drugs that eliminate, or sensitise, populations resistant to secondary therapies, including antibody therapies to small molecules, or combinations.
The North West suffers disproportionately from cancer-associated morbity. We will explore mechanisms that enable cancer cells obtained from human patient samples to survive prolonged exposure to protein kinase inhibitors, key clinical weapons for personalized cancer therapy. This is a strategic Industry:Academic PhD partnership that was ""pump-primed"" by a 2016 University of Liverpool MRC Proximity to Discovery Award, which allowed us to generate important preliminary findings. These data confirm that cell populations that generate drug-resistance in patients treated with kinase inhibitors exhibit unique genetic profiles distinct from those in acutely-dosed patients, and their identification provides an exciting new opportunity for targetting mechanisms of drug-resistance in cancer patients.
Background:
Prolonged treatment of cancer cells with kinase inhibitors leads to transcriptional 're-wiring' of kinase signalling networks. This pathway 'evolution' can be analysed by nanoString-based mRNA kinome profiling and proteomics, quantitative technologies we are developing in Liverpool for personalized cancer cell profiling. Through a recent collaboration with the MRC-PPUU (University of Dundee), we have established that under acute and prolonged conditions of kinase inhibitor exposure, different protein kinase mRNAs are upregulated, and that one can substitute for drug-inhibited pathways (Bago et al., 2016, EMBO J. 35, 9802). This finding has significant consequences for deciding how, and when, combinations of therapeutics should be given to stratified patients. What is missing is understanding of the mRNA and proteomic kinase signatures found in patient-specific cancers, and its prognostic or diagnostic potential in oncology. This MRC DiMeN PhD studentship supports an established collaborative network, and includes skill-set training outside the academic environment with AstraZeneca. This successful pharmaceutical team contributed to the development of Tagrisso/Omisertinib for metastatic non-small cell lung cancer, the fastest protein kinase inhibitor to receive approval in terms of passage from trials to its regulatory approval in 2016.
Studentship work package:
We will evaluate response and resistance 'signatures' found in clinically-relevant cancer cell panels challenged with clinical kinase inhibitors. These patient-derived cells are part of a unique AstraZeneca panel. Data produced from our Industry and academic partnership will inform how whole-kinome analysis can be used to individual patients' advantage. Specifically, it has the potential to increase the therapeutic potential of targeting drug-resistant persistors in various human cancers.
Overall PhD studentship outcomes could include:
1) Provide PhD student(s) with collaborative research training in academic and non-academic settings of stratified medicine excellence but with different technological strengths. To include ~3 months placement at AZ to maximize generic and transferable skills.
2) Strengthen collaborations between DiMeN Universities and help position Liverpool as a training centre of excellence for kinome-based screening of drug-treated tumour samples.
3) Whole kinome expression data for clinical compounds in ~50 patient-derived cancer cell lines of known genomic and drug-responsiveness.
4) Whole kinome dynamics, and selected phosphoproteomics for clinical compounds after i) acute and ii) prolonged compound exposure at a concentration where target engagement is known.
5) Screening of AZ and commercial drug libraries for drugs that eliminate, or sensitise, populations resistant to secondary therapies, including antibody therapies to small molecules, or combinations.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/R502339/1 | 01/10/2017 | 31/08/2022 | |||
| 1961582 | Studentship | MR/R502339/1 | 01/10/2017 | 31/03/2021 | Emma Fairweather |
| Description | UGA Franklin college |
| Organisation | University of Georgia |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Previous work between the Eyers (UoL) and Kannan (UoG) labs has led to the publication of eight research papers, which have fundamentally advanced our understanding of how kinases are regulated. I wish to examine how, and why, drug resistance occurs in tyrosine kinases. This will be achieved by using multidisciplinary approaches that combine skills and techniques from both labs in the broad areas of enzymology, protein biochemistry, computational and structural bioinformatics. |
| Collaborator Contribution | By using state-of-the-art computational methods at the University of Georgia, I am investigating how point mutations in ABL and EGFR directly influence the conformation of the proteins, including how they transition from active to inactive states, and how resistant mutations perturb inhibitor binding |
| Impact | The specific research I propose to pursue in Kannan's lab at UoG involves characterizing effects of mutations found in the ABL and EGFR tyrosine kinases associated with patient drug relapse. This will allow us to understand how these mutations directly influence the structure of these kinases, and the binding and efficacy of FDA-approved drugs for the treatment of chronic myeloid leukaemia (CML) and non-small cell lung cancer (NSCLC). |
| Start Year | 2018 |