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Underlying cause of vemurafenib-induced squamous cell carcinoma discovered
Researchers have identified the mechanism of action that causes the BRAF inhibitor vemurafenib to accelerate the occurrence of secondary squamous cell carcinomas.
Patients treated with vemurafenib (Zelboraf, Genentech) have a BRAF mutation; however, this new study indicates that they also have a secondary mutation that is activated by treatment with vemurafenib.
Prior research has shown that about 25% of people who were undergoing treatment for melanoma with vemurafenib were subsequently developing squamous cell carcinoma. Although most of these carcinomas could be removed surgically, researchers sought to discover the association between the drug and the secondary cancer.
They performed a molecular analysis in skin lesions for patients who were undergoing treatment with vemurafenib. Specifically, they were looking for the mutations HRAS, KRAS, NRAS, CDKN2A and TP53.
Among the 21 tumor samples obtained and tested, 13 had RAS mutations. The researchers then validated this in a second set of tumor samples and found that of the 14 in the validation set, eight had RAS mutations. In total, 60% of the tumor samples had a RAS mutation present.
The researchers found that blocking the non mutated BRAF in cells with mutated RAS caused them to send signals around BRAF that induced the growth of the squamous cell cancers.
In an accompanying editorial, Ashani T. Weeraratna, PhD, said this study should serve as a reminder to researchers that it is important to understand the mechanism of action of targeted therapies; however, she was positive about the results of the study.
“BRAF inhibition is an excellent platform for personalized medicine, since resistance and secondary tumor development can largely be predicted from the changing molecular profile of the patients,” she wrote. “The lessons we are learning from BRAF inhibitors will pave the way for future targeted therapies in other types of cancers.”
For more information:
- Su F. N Engl J Med. 2012;366:207-215.
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A unique feature of RAF inhibitors is their ability to induce squamous cell carcinoma (SCC) of the skin. The spectrum of these lesions range from actinic keratoses to well-differentiated keratoacanthoma-like SCC to classic invasive SCC. These cutaneous neoplasms were first reported in patients treated with sorafenib, a non-selective RAF inhibitor. SCCs occurred in approximately 6% to 7% of patients at a median onset of 6.7 months. Interestingly, the incidence of SCCs increased significantly with the selective BRAF inhibitors, 31% with vemurafenib and 12% with GSK2118436. Moreover, with selective BRAF inhibitors, these skin lesions appeared much earlier when compared with sorafenib. Combining the clinical observations and functional analysis, the researchers provided evidence suggesting that vemurafenib does not initiate tumorigenesis but rather accelerates the progression of pre-existing subclinical cancerous lesions with paradoxical MAPK-pathway activation. This paradoxical activation apparently can be avoided by a MEK inhibitor. The markedly decreased incidence of skin toxicity has also been observed in phase 1/2 clinical trials combining GSK2118436 with a MEK inhibitor. Thus, the combination of a BRAF inhibitor with a MEK inhibitor not only has the potential to overcome drug resistance of BRAF V600-mutant metastatic melanoma, but also can prevent common skin toxicity.
– Wen-Jen Hwu, MD
HemOnc Today Editorial Board member
Disclosure: Dr. Hwu reports no relevant financial disclosures.