The most common adverse events occurring during Vemurafenib treatment and impacting on the quality of life are skin reactions. So far, no detailed investigation of cutaneous side effects of Vemurafenib accompanied by biopsies has been reported. 
We analyzed cutaneous side effects under BRAF inhibitors in 28 consecutive patients, focusing on reaction patterns and time of appearance. An attempt to classify these cutaneous adverse events was made in order to facilitate clinical follow-up and diagnosis in a clinical setting.
There was a peculiar sequence of skin reactions with maculopapular exanthema sparing the face in the first four weeks, photosensitivity that occurred in 16 of 28 patients despite the strict recommendation to use sun screens and pruritus in 8 of 28 patients. The photosensitivity is UVA induced and has significant effect on the patient’s quality of life.
Cutaneous reaction 3–6 weeks after treatment initiation (, ) included inflammatory diseases like maculopapular exanthema, folliculitis and others, dystrophic hair- and nail changes and keratinocytic neoplasms. Late side effects (over 6 weeks on treatment) consisted mainly of keratinocytic proliferations, especially acanthopapillomas and keratoacanthomas as well as keratosis pilaris and hair dystrophies.
Alarmingly, second primary melanomas have been found in an unexpected high frequency 
The paradox of new malignancies such as keratoacanthoma and squamous cell carcinoma has attracted intensive research. Oberholzer et al. have shown that 21% of squamous cell carcinomas and keratoacanthomas presented activating RAS mutations. 
In addition, Su et al. confirmed that mutations in RAS, particularly HRAS, are frequent in keratoacanthomas and squamous cell carcinomas in patients treated with Vemurafenib. 
They have elegantly demonstrated that activated RAS will result in a paradoxical activation of MAPK signaling accelerating tumor growth in BRAF wild type lesions. This suggests that RAS activation is the key event for the progression of keratoacanthomas and squamous cell carcinomas. Homodimer and heterodimer formation involving all members of the BRAF family seems to be involved. 
In case of wild type RAS, an activating signal upstream of RAF such as a mutated EGF-R might drive keratoacanthoma and squamous cell carcinoma proliferation. We have found evidence of a remarkably increased proliferation of keratinocytes shown by immunohistochemistry during the early maculopapular rash, which suggest an increased proliferation rate in the epidermis and follicular structures compared to normal skin.
We argue therefore that other manifestations of the spectrum of skin eruptions depend on RAS activation and therefore might be called RASopathic.
The term RASopathy was introduced to classify a group of syndromes with activating RAS/MAPK germline mutations including cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Noonan syndrome and others. 
These rare genetic syndromes present multisystem disorders with characteristic coarse facial appearance, intellectual disabilities, tumor predisposition and a spectrum of cutaneous alterations that overlap with Vemurafenib associated skin lesions. 
Besides squamous cell carcinomas and keratoacanthomas, many patients present benign keratinocytic neoplasias that are acanthopapillomas or seborrheic keratosis by histology. FGF-R mutations have been found in seborrheic keratosis to be able to activate the pathway. 
Patients with CS and CFC typically present with acanthopapillomas generally located on the face, especially around the nose.
Keratosis pilaris, plantar pressure dependent hyperkeratosis and dystrophic curly hair with slow growth are common in patients affected by CS or CFC and in Vemurafenib treated patients. The callus like palmo-plantar hyperkeratosis without significant inflammation must be carefully distinguished from the palmoplantar dysethesia syndrome that is a typical and often a dose limiting adverse event during VEGF targeting small molecules such as sunitinib and sorafenib.
Keratosis pilaris, cyst formation and plantar hyperkeratosis might be increased by a dysregulation of the fine tuning of the pathway after physiological stimulation. All the three are classical symptoms of RASopathies.
These cutaneous alterations in addition to squamous cell carcinoma and keratoacanthoma are also observed during sorafenib therapy. 
This paper suggests an induction of keratinocytic hyperproliferation by sorafenib without signs of apoptosis resulting in increased epidermal thickness in normal skin. This probably contributes to the clinical presentations of keratosis pilaris and plantar hyperkeratosis. It appears as the opposite of the reaction pattern induced by MEK inhibitors. MEK inhibition results in a suppression of the pathway in keratinocytes resulting in a stress reaction with up-regulation of p53 and a release of cytokines attracting inflammatory cells with the clinical presentation of the typical maculopapular and pustular rash observed during the use of MEK inhibitors. 
The dystrophic hair growth with curly thin hairs often associated with a change of the hair color is often referred to as alopecia. However, it is definitely different to the hair loss seen during chemotherapy. It occurs slowly and complete baldness was not observed in our patients.
As the number of Vemurafenib-treated patients will increase in the near future, it is important to understand the cutaneous side effects of this drug. It is essential to distinguish them from allergic drug reactions. Further classification will facilitate the development of follow-up schedules and clinical management. We propose to conduct detailed dermatological examinations of the skin every 4 weeks during Vemurafenib therapy. Patients should be well informed of the expected cutaneous side effects, especially about the UVA photosensitivity. The use of UVA optimized sunscreens and UV blocking clothing should be strongly recommended, since testing and experience show a prophylactic effect. 
In the future, topical application of the vitamin D derivate calcipotriol and/or retinoids appears promising to normalize the epidermal hyperproliferation. 
Further there are observations of decreased appearing of inflammatory and neoplastic skin lesions when BRAF inhibitors like vemurafenib are combined with MEK Inhibitors. 
Placebo controlled trials will help to investigate the benefit of these co-medications.