Melanoma cells rewire to resist drug treatment

September 27, 2017, University of Pennsylvania
An immunofluorescence image of a melanoma cell stained with antibodies against the cytoskeleton components indicate their invasion into surrounding matrix. Credit: Yueyao Zhu and Wei Guo

In 2014, new combination therapies to treat patients with metastatic melanoma hit the market, helping extend the lives of those with this aggressive disease. Yet unfortunately, after several months of treatment, almost all patients on the regimen eventually relapsed.

A study out this week in Nature, led by scientists from the University of Pennsylvania and The Wistar Institute, reveals why these relapses occur. While the combination therapies block off the principal that cancer cells use to fuel their growth, the cells come to bypass this blockade and, like vehicles on a detour route, make use of additional pathways to continue growing and spreading.

"The tumor cells are smart," said Wei Guo, co-corresponding author on the study and a professor of biology in Penn's School of Arts and Sciences. "Once they block this first pathway, then other pathways can get activated, leading to an even more aggressive disease."

These parallel pathways, governed by the PAK family of enzymes, present appealing new targets for melanoma treatment.

"Our findings provide a possible flanking strategy to counteract the ability of melanoma cells to re-wire their signaling networks," said co-coresponding author Meenhard Herlyn, Caspar Wistar Professor in Melanoma Research and director of the Melanoma Research Center at The Wistar Institute. "When cancer gets smart, we have to act even smarter."

Guo and Herlyn collaborated on the work with co-corresponding authors Xiaowei Xu, a professor of pathology and laboratory medicine and dermatology at Penn's Perelman School of Medicine. The lead authors on the paper are Hezhe Lu and Shujing Liu of Penn and Gao Zhang of Wistar.

Around half of all melanomas are attributable to a mutation in a gene caled BRAF. When mutated, BRAF, an enzyme that acts in a signaling cascade known as the MAPK/ERK pathway, becomes overactive and leads to increased cellular growth, a hallmark of cancer. Accordingly, drugs have been developed to inhibit BRAF. These therapies have been modestly successful, but some patients fail to respond entirely and those who do respond almost inevitably develop resistance.

To bolster the effects of the BRAF inhibitors, recently a new class of drugs was developed to block an enzyme that acts downstream of BRAF/MEK. Pairing the BRAF inhibitor with the MEK inhibitor has given patients with advanced melanoma one of their best treatment options to date. But like the BRAF-inhbitors, the effectiveness has been transient.

Several years ago, Guo and his postdoctoral researcher, Lu, were fascinated to find that drug-resistant melanoma cells were more aggressive than their parental strains in cell-culture assay. To uncover how this resistance occurs, Guo and Lu teamed with Xu, Herlyn and colleagues examined both cell lines and tumor biopsies from melanoma patients before and after either BRAF inhibitor therapy or BRAF/MEK inhibitor combination therapy. As other groups had previously shown, they found that treatment with BRAF inhibitors alone seemed to reactivate ERK, which is downstream of BRAF in the MAPK pathway.

But in many cell lines and patient samples that developed resistance to the combination therapy, the researchers observed something different happening. ERK was not reactivated. Instead, they found that a parallel pathway, governed by the enzyme PAK, was energized.

"We found not only was PAK activated in many patients, but also PAK's downstream targets," Guo said.

Treating cells resistant to combination therapy with a PAK inhibitor reduced their ability to grow. When the researchers did the opposite, turning on a PAK protein in a cell line, they found the became even more resistant to inhibitors of the MAPK pathway.

PAK proteins allow melanoma to thrive through their action on a few different pathways, both encouraging cell cycle progression and inhibiting apoptosis, a form of cell death, the researchers found.

Interestingly, cancer researchers had previously attempted to block PAK as an anti-tumorigenic strategy in the past, only to find it didn't seem to do anything to stop melanoma progression.

"It seems it is only when the ERK pathway is inhibited that PAK becomes 'awake,'" Guo said. "Then you can apply the PAK inhibitor and see an effect."

"Our discovery may direct new drug development efforts to target PAKs," said Xu.

Looking to the future, the Penn-Wistar team sees promise in targeting PAKs as an additional tool to target melanoma tumors. They are following up on some of the parallel pathways downstream of PAK to determine how they operate, and are also pursuing research into immunotherapy approaches in treatment.

Explore further: Link established between a molecular driver of melanoma and novel therapeutic agent

More information: Hezhe Lu et al, PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas, Nature (2017). DOI: 10.1038/nature24040

Related Stories

Link established between a molecular driver of melanoma and novel therapeutic agent

September 7, 2017
Results of a study by The Wistar Institute have described a correlation between a key melanoma signaling pathway and a novel class of drugs being tested in the clinic as adjuvant therapy for advanced melanoma, providing useful ...

Tumor-infiltrating B lymphocytes promote melanoma progression and resistance to therapy

September 19, 2017
In a multi-institutional collaborative study, scientists at The Wistar Institute and the Medical University of Vienna, Austria, have identified the role of tumor-infiltrating or tumor-associated B-cells ("TABs") in melanoma ...

New insight into drug resistance in metastatic melanoma

June 3, 2014
(Medical Xpress)—A study by scientists in Manchester has shown how melanoma drugs can cause the cancer to progress once a patient has stopped responding to treatment.

Blocking melanoma's escape: Avatars break theraping resistance in relapsed cancers

January 7, 2016
Melanoma patients who receive treatment with targeted therapies experience an initial response that feels like a cure, but that early excitement is quickly dampened when patients relapse as their cancers find alternative ...

Preclinical study indicates potential for novel inhibitor to overcome drug resistance induced by RAF, MEK inhibitors

April 8, 2013
A new class of investigational medicines may help to treat patients with cancers driven by mutations in genes such as BRAF or KRAS/NRAS, including those patients who have become resistant to therapies that target BRAF directly, ...

Enhanced treatment, surveillance needed for certain melanoma patients to prevent secondary cancers

August 14, 2013
Moffitt Cancer Center researchers suggest secondary cancers seen in melanoma patients who are being treated for a BRAF gene mutation may require new strategies, such as enhanced surveillance and combining BRAF-inhibitor therapy ...

Recommended for you

Compound in citrus oil could reduce dry mouth in head, neck cancer patients

May 21, 2018
A compound found in citrus oils could help alleviate dry mouth caused by radiation therapy in head and neck cancer patients, according to a new study by researchers at the Stanford University School of Medicine.

Ice cream funds research showing new strategy against thyroid cancer

May 21, 2018
Anaplastic thyroid cancer is almost uniformly fatal, with an average lifespan of about 5 months after diagnosis. And standard treatment for the condition includes 7 weeks of radiation, often along with chemotherapy.

Bladder cancer model could pave the way for better drug efficacy studies

May 21, 2018
Understanding that not all bladder cancers are the same, researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have created a tool that may help them to uncover why only a fraction of patients ...

Breath test breakthrough for early diagnosis of oesophageal and gastric cancer

May 18, 2018
A breath test can successfully detect oesophageal and gastric cancer and could be used as a first-line test for patients, say researchers.

MR spectroscopy imaging reveals effects of targeted treatment of mutant IDH1 gliomas

May 18, 2018
Using a novel imaging method, a Massachusetts General Hospital (MGH) research team is investigating the mechanisms behind a potential targeted treatment for a subtype of the deadly brains tumors called gliomas. In their report ...

Particle shows promise to prevent the spread of triple-negative breast cancer

May 18, 2018
USC researchers have pinpointed a remedy to prevent the spread of triple-negative breast cancer. Metastatic breast cancer is a leading cause of death for women. The findings appear today in Nature Communications.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.