Page 18 - Read Online

Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 273

15. Chromosomal instability, tumour evolution and treatment resistance

Geoff Macintyre

CRUK Cambridge Institute, Cambridge, UK

Tumours with chromosomal instability exhibit increased intratumoral heterogeneity and poor prognosis.
Genetically distinct clones enable a wider sampling of the fitness landscape, increasing the chance of rapid
progression and treatment resistance. Here, I will present our recent work on identifying different types of
chromosomal instability through copy number signature analysis. I will highlight the role that chromo-
somal instability plays in tumour evolution and the challenges faced trying to move mutational signature
analysis into the clinic.

16. Intra-tumour signalling and targeted therapy in melanoma

Claudia Wellbrock

University of Manchester, UK

The BRAF-kinase and the MAPK-pathway are targets of current melanoma therapies, where they can in-
duce fast responses with minimal adverse effects. Our recent work has demonstrated that intra-tumour
signalling can have a major impact on the efficacy of MAP-kinase pathway targeting drugs. We discov-
ered that the melanoma-specific transcription factor MITF confers cell-autonomous resistance to MAPK
pathway therapy. Recent work by others has also demonstrated that MITF is an essential survival factor
for drug-addicted acquired resistant melanomas. We found that during treatment with BRAF and MEK
inhibitors, MITF expression is up-regulated in responding tumours and as direct consequence of effective
inhibition of the MAPK pathway. This MITF up-regulation during treatment counteracts the killing-effect
of the drugs, thus initiating a phase of tolerance to treatment which allows acquired resistance to establish.
We identified the HIV-protease inhibitor nelfinavir as an inhibitor of the drug-induced MITF up-regula-
tion. In line with this activity, nelfinavir profoundly improves responses to MAP-kinase pathway targeting
drugs in BRAF and NRAS mutant melanoma. One of the major challenges in tackling acquired resistance
to MAPK inhibitors is the phenotype heterogeneity found in melanoma. As such melanomas contain sub-
low
high
populations of cells that can be described as MITF and MITF . We had shown previously that MITF-
phenotype heterogeneity is of advantage for melanoma invasion, but we revealed that it also contributes
to the establishment of highly resistant tumours. We identified a novel mechanism based on intra-tumour
communications that maintains phenotype heterogeneity, and targeting this mechanism overcomes het-
erogeneity driven resistance in melanoma.

17. The NF-κB regulated gene, Claspin, is potential biomarker for the response to Chk1

inhibitors

1
3
2,3
1
Jill E. Hunter , Jacqueline A. Butterworth , Michelle D. Garrett , Ian Collins , Neil D. Perkins 1
1 Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle
Upon Tyne, Newcastle NE2 4HH, UK
2 School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
3 The Institute of Cancer Research, Sutton SM2 5NG, UK