We conclude that a subset of FVPTC shares some of the molecular features of follicular tumors. Further studies are necessary to clarify the putative clinical significance (e.g. association to blood-born metastases) of PAX8-PPARgamma rearrangement, RAS mutations, and BRAF(K601E) in FVPTCs.

Summary We show that imatinib, nilotinib and dasatinib possess weak off-target activity against RAF and therefore drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, since RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cell in vitro and in vivo.

Due to their different molecular alterations, these cell lines represent a valuable tool to study the molecular mechanisms underlying thyroid carcinogenesis. We suggest that genotypic analyses should be included as a routine procedure to guarantee the uniqueness of each cell line used in research.

Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.