Wednesday, August 14, 2013

BRAF, Melanoma, and Unintended Consequences

The introduction of the BRAF inhibitors has been lauded as a significant breakthrough in melanoma treatment. Of the 40-50% of patients with the BRAF V600 mutation it has prolonged life, albeit for a limited amount on average. However there has been observed secondary cancers putatively resulting from the use of the therapeutic. Logically RAF and specifically BRAF are common in many cells and one would expect even a mutated form elsewhere.

 Recent Results

Now Gibney et al state: 

The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps.In most cases, paradoxical MAPK activation—resulting from the BRAF-inhibitor-mediated homodimerization and heterodimerization of nonmutant RAF isoforms—seems to underlie the development of these secondary tumours. Although evidence supports that therapy with the simultaneous administration of BRAF and MEK inhibitors abrogates the onset of treatment-induced SCCs, whether combination treatment will limit the emergence of all BRAF-inhibitor-driven pathologies is unclear.In this Review, we describe the clinical and mechanistic manifestations of secondary cancers that have thus far been observed to arise as a consequence of BRAF inhibition. We discuss the concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.

These observations are a warning which should be heeded in therapeutics which albeit targeted are still broad based.

Newswire states: 

However, a type of cellular signaling caused by the BRAF inhibitors may leave patients susceptible to secondary malignancies, such as squamous cell carcinoma and RAS-mutant leukemia. “These secondary cancers emerge because BRAF inhibitors can activate tumor growth pathways in cells with genetic changes,” 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.

This clearly demonstrates the need for better pathway dynamics models and prediction. We arguably know the key parts but there are other parts whose activation we yet understand.


Unintended consequences are quite common. These are useful in several ways.

First, they help better understand the pathways dynamics and perhaps extend the therapeutic methodology to track the unintended consequences and head them off at the pass.

Second, and here I think specifically of azacytidine and MDS, using a hypomethylation therapeutic to attack a hypermethylated cell, to restore normal homeostasis may have systemic effects. The use of hypomethylation therapeutics will not only attack the aberrant cells but frankly everything else. Thus the unintended consequences may be delays but could be substantial.

Third, in a sense these become in vivo petri dishes for examining pathway aberrations. Thus it is imperative to think about the consequences ab initio and just as importantly be prepared to understand the consequences a posteriori.

Fourth, have a set of therapeutics targeted to counter the possible negative consequences would be imperative.

Fifth, using the secondary cancers one has the opportunity to examine pathway induced cancers. Thus capture of the genetic as well as epigenetic information is critical.


Gibney G., et al, Paradoxical oncogenesis—the long-term effects of BRAF inhibition in melanoma, Nature Reviews Clinical Oncology 10, 390-399 (July 2013),