Download ROCK (Rho-associated protein kinase)

Title: ROCK (Rho-associated protein kinase) inhibition sensitizes NRAS mutant melanoma to
MAPK pathway inhibitors in vitro and in vivo
Field of use:
Therapeutics; Combination Therapy; N-RAS mutated tumours; Melanoma
Key Benefits:
 Therapy for N-RAS mutated cancers
 Effective Therapy to overcome resistance to targeted therapies
Background:
Malignant melanoma is a highly aggressive cancer. About 132,000 melanoma skin cancers occur
globally each year, with rising incidence worldwide due to continued exposure to risk factors. Once
metastasized, Melanoma is notoriously difficult to treat. The most commonly mutated genes in
cutaneous melanoma are BRAF and NRAS. Vemurafenib, a recently approved inhibitor of the mutant
V600E
oncogenic kinase BRaf
present in 50% of cutaneous melanoma, leads to spectacular remissions,
but most patients relapse within months. There is currently no approved targeted therapy for NRAS
mutant melanoma. Various MEK inhibitors are tested in clinical studies (e.g. Trametinib
(GlaxxoSmithKline, already FDA-approved for BRAF mutant melanoma), MEK162 (Novartis)).
However, responses were even more short-lived than reported for Braf inhibition, since resistance of
tumors to single targeted therapies invariably emerges. As such, MEK inhibitors such as the FDAapproved trametinib (GSK1120212) will probably currently be most effective as melanoma therapy in
combination with other targeted agents to counteract intrinsic and acquired resistance.
Invention:
We identified ROCK inhibitors (GSK269962A, Fasudil) as sensitizers to a MEK inhibitor
(GSK1120212) in a panel of treatment-naïve NRAS mutant melanoma cell lines and show efficacy of
the combinations in mouse models and a xenografted NRAS mutant melanoma cell line.
We identified inhibitors from a panel of established drugs and tool compounds as sensitizers to
trametinib. We tested the agents alone and in combination with MAPK pathway inhibitors in a panel of
treatment-naïve NRAS mutant melanoma lines. The best performing combination enhanced apoptosis
(increased caspase 3 and PARP cleavage and BimEL levels) and reduced phospho-S6RP levels. It
also suppressed outgrowth of a xenografted NRAS mutant melanoma line.
Our findings suggest that the use of MEK inhibitors in combination with inhibitors targeting other
specific pathways allows for a more durable response of both treatment-naïve melanomas and
melanomas with acquired resistance to MAPK pathway targeting therapies. We suggest a combination
of MEK inhibitor plus ROCK inhibitor.
1
Figure 1B: Combination of ROCK inhibitor GSK269962A with a MEK inhibitor inhibits melanoma cell proliferation Figure 1C: Combination of ROCK inhibitor Fasudil with a MEK inhibitor inhibits melanoma cell proliferation B C
DMSO MEKi ROCKi (GSK) MEKi + ROCKi BLM SK‐MEL‐103 SK‐MEL‐147 Figure 2 A, B: ROCK inhibitor increases MEK‐inhibitor induced effects on tumor growth in vivo (at low (A) and high (B) doses of MEK inhibitor) in mice. A: B:
Relative growth
Relative growth Time after treatment (days) Time after treatment (days)
Intellectual Property: Priority application filed on September 20 2012
Key researchers: (Name, title, institute and department)
Prof Daniel Peeper, Dr. Celia Vogel, Dr. Marjon Smit The Netherlands Cancer Institute. Department of
Molecular Oncology.
Website:
http://research.nki.nl/peeperlab/
http://www.nki.nl/
Contact Information:
Dr. Marije Marsman
Business Developer NKI-AVL
0031205126071
[email protected]
2