Professor Spiros Linardopoulos, Drug Target Discovery team
The 'Aurora' programme was initiated as part of the basic research and drug discovery programmes to investigate the role of Aurora kinases in oncogenesis and to discover Aurora kinase inhibitors as therapeutic drugs. Throughout this work, CCT241736 was discovered [Bavetsias et al 2012]. CCT241736 is a novel, potent, orally bioavailable dual Aurora/FLT3 kinase inhibitor that selectively inhibits the Aurora and FLT3 pathways in vitro and in vivo. We have generated acute myeloid leukemia (AML) cell lines resistant to FLT3 selective inhibitors and we have demonstrated that our Aurora/FLT3 inhibitors overcome this resistance [Moore et al, Leukemia 2012]. CCT241736 is now in the final stages of development and we aim to enter Phase I trials in AML.
Based on studies in our laboratory, we selected MPS1 as a target in drug discovery to treat breast cancer. Collaborative studies in the Breast Cancer Centre have shown that certain subtypes of breast cancer cell lines are particularly sensitive to MPS1 down-regulation and constitute clinical target populations for an MPS1 inhibitor. We have further validated MPS1 as target in cancer in different biochemical and cellular models and a drug discovery programme was initiated (2006) in the Cancer Therapeutics Unit. In addition, we have identified that inhibition of MPS1 in combination with paclitaxel treatment of TNBC cell lines at clinically-relevant concentrations induces synergistic cell death. The MPS1 preclinical development candidate CCT289346 is currently in the development stage and we aim to enter Phase I clinical trials in triple negative breast cancer in combination with paclitaxel.
As part of basic research, we recently published significant findings focusing on drug resistance. We have generated and characterised, resistant mutant cell-clones to a variety of MPS1 inhibitors to examine how these mutants are. Importantly, we showed that these mutations occur in non-treated cancer cell lines and primary tumour samples and also pre-exist in normal breast tissues and lymphoblast. Our data suggested that mutations conferring resistance to targeted therapy are naturally occurring mutations in normal and cancer cells. To translate these data into drug discovery, we have designed MPS1 inhibitors that specifically target these resistant mutants as a second line therapy arising [Gurden et al, Cancer Res 2015].
In addition, we investigated the roles of MPS1 and Aurora B in spindle assembly checkpoint (SAC) and we have shown that MPS1 and Aurora-B kinases are involved in distinct mechanisms of this checkpoint. We demonstrated that the major role of Aurora B in SAC is to maintain the checkpoint active by preventing the removal of proteins from kinetochores, whereas MPS1 is responsible for the initiation of SAC. These findings highlight a therapeutic strategy through combination of Aurora B and MPS1 inhibitors [Gurden et al, Oncotarget 2016].
Centrosome de-clustering HSET and APC/CCDH1
The clear need of novel treatments in particular cancers, such as centrosome-amplified aneuploid cancers, has recently led us to identify new targets for anticancer drug discovery. Supernumerary centrosomes have been detected in virtually all human cancers, are associated with many tumour phenotypes (e.g. p53 loss, BRCA1/2 mutation, Aurora amplification) and are implicated in multipolar mitosis, genomic instability and aneuploidy. Our siRNA screen demonstrated that cancer cell lines with centrosome amplification are selectively sensitive to depletion of HSET/KIFC1 kinesin and APC/C E3 ubiquitin ligase, inferring a role for these proteins and complexes in regulating centrosome clustering.
HSET has been well-validated as a therapeutic target in cancer. We have established a close collaboration with Prof Andrew Tutt, at the Breast Cancer Now and Kings College London, who independently identified HSET as a potential target in a centrosome-amplified breast cancer cell line screen. My laboratory, in collaboration with Professors Ian Collins and Andrew Tutt and Cancer Research UK Discovery Laboratory, has commenced a programme to discover small molecule inhibitors of HSET to treat centrosome-amplified cancers.
An additional project aimed to identify the mechanisms underlying centrosome clustering in centrosome-amplified cancer cells. We found that APC/CCDH1 is a major regulator of the Eg5 kinesin in this process. Our results reveal an essential pathway for the fate of centrosome-amplified cancer cells, a major characteristic of breast cancer cells, the inhibition of which may have important therapeutic implications [Drosopoulos et al, Nat Commun 2014].