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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 289

42. Myosin II reactivation and cytoskeletal remodelling as a hallmark and a vulnerability in
melanoma therapy resistance

1,5
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4
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Jose L. Orgaz , Maria Romina Girotti , Eva Crosas-Molist , Amine Sadok , Anna Perdrix-Rosell ,
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2
Irene Rodriguez-Hernandez , Silvia Mele , Florencia Veigas , Mirella Georgouli , Victoria Bridgeman ,
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3
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Panagiotis Karagiannis , Pahini Pandya , Lena Boehme , Matthew Smith , Gabriela Gremel , Rebec-
1,6
3
3
3
ca Lee , Elena Galvani , Franziska Baenke , Paul C. Lorigan7, Fredrik Wallberg , Amaya Viros , Ilaria
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Malanchi , Sophia Karagiannis , Richard Marais , Victoria Sanz-Moreno
1
1 King’s College London, London, UK
2 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
3 Cancer Research UK Manchester Institute, Manchester, UK
4 The Institute of Cancer Research, London, UK
5 The Francis Crick Institute, London, UK
6 University Hospital of Hamburg Eppendorf, Hamburg, Germany
7 The University of Manchester, Christie NHS Foundation Trust, Manchester, UK
Targeted and immunotherapies improve survival of a proportion of melanoma patients. However, lack of
response or therapy resistance are persistent problems in melanoma management. In this study, we provide
evidence that early adaptation to treatment and acquisition of resistance to MAPK inhibitors (MAPKi) in-
volve profound cytoskeletal remodelling. This is concomitant with changes at the transcriptomic and phos-
pho-proteomic level of many cytoskeletal proteins. Most significant changes are observed in the ROCK-
Myosin II pathway, widely studied for its key role in cancer invasion and metastasis. Furthermore, we find
that MAPK signalling itself positively controls Myosin II activity. After initial therapy response, drug-
resistant clones restore MAPK and, in turn, Myosin II levels by increasing expression of myosin light chain
2, ROCK, LIM kinase and myocardin-related transcription factor. Cross-resistance to MAPKi and immune
checkpoint inhibitors has been recently proposed to be controlled by common transcriptomic alterations.
We report that high ROCK-Myosin II activity and its characteristic transcriptome identify both targeted-
and immunotherapy-resistant melanomas. Importantly, resistant cells are more dependent on Myosin II
activity for their survival. ROCK1/2 or Myosin II activity blockade with either small molecule inhibitors or
RNAi depletion induces death of resistant cells through a combination of cell cycle defects and decreased
survival signals. Furthermore, efficacy of both targeted and immunotherapies can be greatly improved by
combining such therapies with ROCK inhibitors in vivo. Therefore, we propose that a subset of targeted
and immunotherapy-resistant melanomas is more vulnerable to ROCK-Myosin II inhibition, which opens
up clinical opportunities for combination therapies. This work is currently under revision for Cancer Cell.

43. HIF-mediated suppression of DEPTOR confers resistance to mTOR kinase inhibition in

renal cancer

Jogitha Selvarajah, Shruthi Devkumar, Hong Doan, Alexander Parsons, Francesc Miralles, Ve-
ronica A. Carroll

St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK

Kidney cancer is diagnosed in over 300,000 individuals annually. Most kidney tumours are clear cell renal
cell carcinomas (ccRCC) and metastatic disease is still largely incurable, despite some advances in targeted
therapeutics. However, both intrinsic and acquired drug resistance are major causes of failure of targeted
therapy in ccRCC. Mechanistic target of rapamycin (mTOR) is a fundamental regulator of cell growth and