Pathways, Crosstalk and Melanoma

NEJM has published an interesting article on what can be called cross talk amongst pathways. As is well known now the BRAF mutation found in certain melanomas can be somewhat controlled via the use of vemurafenib. However and possibly surprisingly there is an increase in other cancers.

The authors conclude:

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.

Pathways have cross talk, and when one pulls one string another may also be pulled. The authors further note:

The t→a transversion at position 1799 of BRAF (BRAF V600E) is present in approximately 50% of patients with metastatic melanoma.1,2 BRAF V600E induces constitutive signaling through the mitogen-activated protein kinase (MAPK) pathway, stimulating cancer-cell proliferation and survival.2 The clinical development of inhibitors of oncogenic BRAF, termed type I BRAF inhibitors, which block the active conformation of the BRAF kinase, has led to a high rate of objective tumor responses and improvement in overall survival, as compared with standard  chemotherapy.3-5 However, nonmelanoma skin cancers — well-differentiated cutaneous  squamous-cell carcinomas and keratoacanthomas — have developed in approximately 15 to 30% of  patients treated with type I BRAF inhibitors such as vemurafenib and dabrafenib.

This may open a door to several new approaches. First understanding pathways better and deducing the effects on blocking one of the paths, and multi-drug analysis.