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 with other inhibitors, especially as they become more widely used. They discussed this topic in a review article that appears in the July issue of Nature Reviews Clinical Oncology.

The BRAF gene is mutated in about half of all cases of melanoma, as well as other cancers, and the can be successfully deactivated by BRAF inhibitor drugs. The development and therapeutic use of BRAF to treat patients in advanced stages of BRAF-mutant melanoma is a prime example of a successful targeted therapy. Inhibiting the mutant BRAF protein causes the tumor to shrink. FDA-approved BRAF inhibitors are widely used in metastatic melanoma with much success, and their use is expanding to other tumor types and is being tested in earlier stages of melanoma.

However, a type of cellular signaling caused by the BRAF inhibitors may leave patients susceptible to secondary malignancies, such as and RAS-mutant leukemia.

"These secondary cancers emerge because BRAF inhibitors can activate pathways in cells with ," explained co-author Keiran S. Smalley, Ph.D., assistant member of the Cancer Biology and Evolution Program at Moffitt. "When the BRAF inhibitor signaling activates a biological pathway called MAPK (mitogen-activated protein kinases), secondary cancers can emerge."

The researchers call the development of secondary cancers a case of paradoxical activation.

"The paradoxical activation of MAPK signaling was an unexpected observation that emerged as BRAF inhibitors were being developed," said co-author Geoffrey T. Gibney, M.D., assistant member of the Chemical Biology and Molecular Medicine Program at Moffitt. "Combination therapies using BRAF inhibitors and other inhibitors are being considered to prevent paradoxical activation of MAPK pathways."

A possible combination therapy to lessen the risk of paradoxical activation and the emergence of secondary malignancies is combining BRAF inhibitors with other inhibitors. One option is an MEK inhibitor, which inhibits the mitogen-activated protein kinase enzymes used to therapeutically affect the MAPK pathway that is often overactive in cancers. However, this combination does not eliminate all secondary cancers.

The researchers note that extended follow-up for patients showing long-term responses to BRAF inhibitors has often been lacking. They also added that BRAF-mutant melanoma patients with a family history of colorectal cancer may require more than the usual screening if BRAF-inhibitor therapy is necessary.

"Despite the concerns, the development of BRAF inhibitors is a major milestone in treating patients with BRAF-mutant melanoma," concluded study co-author Vernon K. Sondak, M.D., chair of the Cutaneous Oncology Program at Moffitt. "With surveillance and carefully designed drug combinations, the future for patients with BRAF-mutant melanoma and other malignancies looks increasingly optimistic."

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

More information: www.nature.com/nrclinonc/journ … rclinonc.2013.83.pdf

Related Stories

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, ...

BRAF inhibitor treatment causes melanoma cells to shift how they produce energy

March 8, 2013
A multi-institutional study has revealed that BRAF-positive metastatic malignant melanomas develop resistance to treatment with drugs targeting the BRAF/MEK growth pathway through a major change in metabolism. The findings, ...

Second mutation in BRAF-mutated melanoma doesn't contribute to resistance

April 1, 2012
A second mutation found in the tumors of patients with BRAF-mutated metastatic melanoma does not contribute to resistance to BRAF inhibitor drugs, a finding that runs counter to what scientists expected to be true.

BRAF mutation less common among patients with melanoma in Ireland

April 8, 2013
The BRAF mutation believed to drive disease in about half of patients with melanoma was found to occur at a significantly lower frequency in patients with melanoma in Ireland, according to data presented at the AACR Annual ...

New drug, Vemurafenib, doubles survival of metastatic melanoma patients

March 1, 2012
A report published this week in the New England Journal of Medicine shows that the 50 percent of metastatic melanoma patients with a specific genetic mutation benefit from the drug Vemurafenib – increasing median survival ...

Uncommon BRAF mutation in melanoma sensitive to MEK inhibitor drug therapy

July 16, 2012
An uncommon mutation of the BRAF gene in melanoma patients has been found to respond to MEK inhibitor drugs, providing a rationale for routine screening and therapy in melanoma patients who harbor the BRAF L597 mutation.

Recommended for you

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

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.