Analysis of cellular models of clonal evolution reveals co-evolution of imatinib and HSP90 inhibitor resistances.

Treatment relapse due to clonal evolution was shown to be an independent factor for poor prognosis in advanced stages of chronic myeloid leukemia. Overcoming secondary resistance arising due to clonal evolution is still an unmet need and lack of adequate pre-clinical models hampers the identification of underlying mechanisms and testing of alternate treatment strategies. The current study thus aimed to create cellular models to study molecular mechanisms underlying clonal evolution and identify strategies to overcome the secondary drug resistance. Analysis of cell lines derived from three independent cell-based screens revealed the co-evolution specifically of imatinib and HSP90 inhibitor (HSP90i) resistances despite their exposure to a single inhibitor alone. Molecular and biochemical characterization of these cell lines revealed additional cytogenetic abnormalities, differential activation of pro-survival signaling molecules and over expression of ABL kinase and HSP90 genes. Importantly, all the imatinib-HSP90i dual resistant cell lines remained sensitive to sorafenib and vorinostat suggesting their utility in treating patients who relapse upon imatinib treatment due to clonal evolution. In addition, we cite similar examples of dual resistance towards various kinase inhibitors and HSP90i in some cell lines that represent solid cancers suggesting co-evolution leading to secondary drug resistance as a pan-cancer phenomenon. Taken together, our results suggest the efficacy of HSP90i in overcoming drug resistance caused by point mutations in the target kinase but not in cases of clonal evolution.

Rare Disorder of Sexual Differentiation with a Mosaic 46,XX/47,XXY in a Klinefelter Syndrome Individual.

BACKGROUND: Klinefelter syndrome (KS) mosaicism 46,XX/47,XXY is an extremely rare disorder of sex development characterized by the presence of both ovarian and testicular tissues in the same individual. Both elements can be present in the same gonad (ovotestis) or separately in the same individual or as a unilateral ovotestis and the other side with testis or ovary. A mosaic with 46,XY would present with problems related to male infertility and in general, testicular insufficiency, but with a 46,XX mosaic, it is a completely rare presentation. As adolescents, these boys may experience severe emotional and behavioral issues; it is up to the parents to identify these conditions early and get them physician evaluated for possible abnormalities so that they can get the benefit of treatment. CASE PRESENTATION: A case of a rare disorder of sexual differentiation with a mosaic 46,XX/47,XXY in a KS individual is reported for whom karyotyping and SRY-FISH work-up was done. CONCLUSION: Early cytogenetic testing is essential to identify these individuals and testosterone replacement therapy and breast reduction for case management are helpful. Assisted reproductive technology (ART) may assist these individuals father children in some cases.