- Novel investigational
drug dubbed MK-8353 has been developed to block signals such as ERK (Extracellular
Signal-Regulated Kinase) pathway, shown to aid cancer cell growth in
- Advanced melanoma is
aggressive skin cancer and resistance to current therapies makes treatment
shows promise in the treatment of advanced melanoma in early phase
clinical trials, according to a group of scientists at University of North
Carolina (UNC) Lineberger Comprehensive Cancer Center and other institutions.
The findings of the current study undertaken by UNC Lineberger's Stergios
Moschos, MD, and his colleagues appear in the journal JCI Insight.
The early phase I
clinical study involved determining the role of the investigational drug MK-8353 in 26 patients
in BRAF and RAS genes. This drug
was developed to block cancer growth and resistance promoting signals such as ERK (Extracellular Signal-Regulated Kinase)
and other cancers resistant to treatment.
Reason for Current Study - To Overcome Resistance to Current
therapy is approved
for advanced melanoma and lung cancer
with mutations in the BRAF gene that promote cancer growth and spread, but
many of the patients develop resistance and the cancer returns sooner than
‘MK-8353 compound inhibits ERK (Extracellular Signal-Regulated Kinase) pathway believed to play a role in growth and spread of resistant melanoma’
To overcome this resistance,
the study team at UNC Lineberger and other institutions developed the MK-8353 compound to try and inhibit signals that help
, such as a ERK rather than
the early signals that initially trigger the hyperactive growth.
Key Observations of the Study
- Three of the 15
patients showed results consistent to partial responses to the new
Although the study
included only a few participants, the study team believe that the responses are
similar to studies evaluating Mitogen-activated protein kinase kinase (MEK) inhibitors
that block the MEK pathway overactive in
- The low response rates
suggest that combination therapies with the new compound MK-8353 might be
rate that we saw for ERK inhibitors is reminiscent of the response seen with
MEK inhibitors," said Moschos, who is an associate professor in the UNC
School of Medicine. "We think, therefore, that ERK inhibitors cannot be
given as single agents, just like MEK inhibitors. The question is: Which
combination is best?"
- While trying to
establish the safe dose of this drug, the team found that most patients could tolerate treatment
up to 400 milligrams twice daily
Due to the occurrence of toxicities, Moschos feels further
studies trialing alternative dosing
schedules such as once a day regimen or twice a day dose every few days need to
alternative approach may balance higher, though more temporal, suppression of
pERK at the tumor tissue in favor of sparing sustained suppression of ERK
signaling in normal tissues," the researchers reported.
Future Studies Planned
- UNC Lineberger's
Channing Der, PhD, Sarah Graham Kenan Distinguished Professor in the UNC
School of Medicine Department of Pharmacology, has begun work on preclinical studies designed to identify
possible drug combinations that would improve ERK inhibitor anti-tumor activity and minimize
toxicity for patients.
- Based on a promising
combination identified, another
phase I clinical trial study led by UNC Lineberger's Autumn McRee, MD,
associate professor in the UNC School of Medicine, aims to study an alternative investigational ERK inhibitor
combination in pancreatic cancer patients.
stimulates factors that promote cancer growth," Der said. "ERK is
very complex, and it's still surprisingly poorly understood, but what is very
clear is that it is required for cancer
and that's why there are a number of inhibitors in this
pathway that are either approved, or under clinical evaluation. Clearly, drug
companies for good reason have decided that this is an important pathway, let's
make inhibitors against it."
In conclusion, a lot of recent interest generated in the ERK
pathways role in cancer growth and resistance has spurred a series of studies
to develop safe and effective ERK inhibitors targeting this pathway. Whether
they will live up to expectations, only
time will tell.
- Treatment of Metastatic Melonoma: A new World Opens - (https://www.skincancer.org/skin-cancer-information/melanoma/melanoma-treatments/treatment-of-metastatic-melanoma)
- MEK inhibitor - (https://en.wikipedia.org/wiki/MEK_inhibitor)