Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.
The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.1 Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.1,2
Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.3 During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).4 This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al5 reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.
In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.6
The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.7 In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.6
Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.7,10,11
In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.9,12
Zimmer et al1 reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.1