BRAF Inhibitor Therapy Linked to Squamous-Cell Carcinoma in Patients with RAS Mutations

JHOP - March 2012, VOL 2 NO 1 - From the Literature, From the Literature
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy, Touro University–California
Mare Island, Vallejo, CA

Background: As many as 15% to 30% of patients who receive BRAF inhibitors, such as vemurafenib or dabrafenib, for metastatic melanoma develop cutaneous squamous-cell carcinomas and keratoacanthomas (nonmelanoma skin cancer) during their therapy. A new study investigated the nature of the oncogenic mutations in patients with the BRAF V600 mutation who received vemurafenib.  

Design: A molecular analysis was conducted to identify oncogenic mutations, including HRAS, KRAS, NRAS, CDKN2A, and TP53, in lesions from 23 patients with the BRAF V600 mutation in 3 separate studies (phases 1-3, respectively) who received vemurafenib 720 or 960 mg orally twice daily for metastatic melanoma. The analysis included 21 samples of cutaneous squamous-cell carcinoma or keratoacanthoma obtained from 11 patients (mean age, 60 years). In addition, a validation set of 14 samples taken from 12 patients who received vemurafenib therapy was analyzed to confirm the prevalence of RAS mutations.

Summary: A total of 78% of the patients had a history and signs of chronically sun-damaged skin, and 17% had a history of cutaneous squamous-cell carcinomas or keratoacanthomas. The lesions were widely distributed, and 63% were characterized as keratoacanthomas. The mean time to diagnosis of the first lesion was 10 weeks; the earliest appeared at 3 weeks. A total of 13 of 21 of the initial samples and 8 of the 14 validation set samples (60% total) had RAS mutations. Of the lesions with RAS mutations, 12 of the 13 initial samples and 4 of the 8 validation samples had HRAS mutations (most prevalent, HRAS Q61L). The effects of BRAF inhibitors on HRAS mutations were compared by the murine cell line B9, which harbors the HRAS Q61L mutation, before and after exposure in vitro to vemurafenib or its analog PLX4720. Similar tests were conducted with HRAS Q61L expressed in the human squamous-cell carcinoma cell line A431, which harbors wild-type RAS in addition to amplified EGFR, and in NIH3T3 cells, which harbor wild-type RAS without EGFR amplification. In all 3 studies, exposure to vemurafenib led to an increased proliferation of HRAS Q61L mutation caused by an increase in oncogenic MAPK-pathway signaling, as evidenced by increased ERK phosphorylation and increased expression of ERK-regulated genes. The PLX4720 was found to accelerate the growth of the HRAS mutations, which was blocked by concomitant treatment with an MEK inhibitor. Because most tumors appeared on sun-damaged skin relatively quickly after initiating vemurafenib therapy, vemurafenib may not have any direct carcinogenic effects but rather may potentiate a preexisting cancerous process.
 
Takeaway:
Vemurafenib, the recently FDA-approved agent for malignant melanoma, appears to exacerbate preexisting nonmelanoma skin cancer. This report describes the mechanism by which vemurafenib potentiates skin cancers. It appears that the drug enhances MAPK activity leading to RAS gene mutations, a driver oncogene in approximately one third of cancers. This effect can be blocked with the use of MEK inhibitors. This discovery may lead to the development of BRAF inhibitors that lack the ability to stimulate MAPK and RAS mutations.

Su F, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207-215.

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