RASMutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors

Abstract

BACKGROUND Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann–La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.)

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

“…Small-molecule inhibitors of BRAF V600 kinase (vemurafenib, dabrafenib) significantly improved survival compared with chemotherapy in metastatic melanoma with BRAF V600 mutation, though resistance usually occcurs after a median 6-7 months and second malignancies can appear (19,20). BRAF inhibitors can provoke the reactivation of MAPK pathway downstream of BRAF kinase in a ras-dependent manner (21). Paradoxical activation of the MAPK pathway occurs not only in BRAFmutant melanoma cells, but in the BRAF wild-type and rasmutant normal cells driving the appearance of secondary cancers like hyperproliferative cutaneous lesions (21), primary melanoma (22) or leukaemia (23).…”

Targeted therapy for BRAF-mutation positive metastatic melanoma

“…A BRAF inhibitorok specifikus mellékhatásaként benignus (pl. papilloma) és (pre)malignus bőrtumorok (keratoacanthoma, spinalioma 19-26%-ban, második primer melanoma 1,6-2,4%-.ban) alakulhatnak ki (5. ábra), melyek kezelése sebészi eltávolítás, a terápia felfüggesztése nem szükséges (20,23,24). A háttérben a RAS-mutáns, de BRAF vad típusú sejtekben az inhibitor okozta paradox MAPK-útvonal aktiváció játszik elsősorban szerepet.…”

BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

“…Sanger sequencing consists of polymerase chain reaction (PCR) amplification of the DNAís region of interest, limited by dideoxynucleotide end termination, followed by sequence reading. This technique has analytical sensitivity of 10-20% (Su et al, 2012;Lee et al, 2010;Morandi et al, 2012). The Cobas ® is another available method, based on real time PCR, with DNA probes designed specifically to detect V600 mutations: V600E, V600 K, and V600D.…”

“…Hypothetically, BRAF inhibitors exert a paradoxical activating effect over WT BRAF in keratinocytes, leading to cell proliferation and apoptosis inhibition (Su et al, 2012). Concomitant use of MEK and B-Raf inhibitors reduced dramatically the incidence of second cutaneous tumors in melanoma patients, by blocking MAPK pathway in a target downstream than B-Raf Long et al, 2014) (Fig.…”

“…Theoretically, this may reduce the incidence of side effects observed with previous B-Raf inhibitors, especially new cutaneous tumors, which have been associated to WT B-Raf activation in keratinocytes (Su et al, 2012). A phase I/II trial is currently recruiting colorectal and melanoma cancer patients to receive LGX818 (NCT01436656).…”