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- Haq, Rizwan, et al.
(författare)
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BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:11, s. 4321-4326
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Tidskriftsartikel (refereegranskat)abstract
- Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in similar to 30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.
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| 2. |
- Milisavljevic, Dan, et al.
(författare)
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MULTI-WAVELENGTH OBSERVATIONS OF SUPERNOVA 2011ei : TIME-DEPENDENT CLASSIFICATION OF TYPE IIb AND Ib SUPERNOVAE AND IMPLICATIONS FOR THEIR PROGENITORS
- 2013
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 767:1, s. 71-
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Tidskriftsartikel (refereegranskat)abstract
- We present X-ray, UV/optical, and radio observations of the stripped-envelope, core-collapse supernova (SN) 2011ei, one of the least luminous SNe IIb or Ib observed to date. Our observations begin with a discovery within similar to 1 day of explosion and span several months afterward. Early optical spectra exhibit broad, Type II-like hydrogen Balmer profiles that subside rapidly and are replaced by Type Ib-like He-rich features on a timescale of one week. High-cadence monitoring of this transition suggests absorption attributable to a high-velocity (greater than or similar to 12,000 km s(-1)) H-rich shell, which is likely present in many Type Ib events. Radio observations imply a shock velocity of v approximate to 0.13 c and a progenitor star average mass-loss rate of (M) over dot approximate to 1.4 x 10(-5) M-circle dot yr(-1) (assuming wind velocity v(w) = 10(3) km s(-1)). This is consistent with independent constraints from deep X-ray observations with Swift-XRT and Chandra. Overall, the multi-wavelength properties of SN 2011ei are consistent with the explosion of a lower-mass (3-4 M-circle dot), compact (R-* less than or similar to 1 x 10(11) cm), He-core star. The star retained a thin hydrogen envelope at the time of explosion, and was embedded in an inhomogeneous circumstellar wind suggestive of modest episodic mass loss. We conclude that SN 2011ei's rapid spectral metamorphosis is indicative of time-dependent classifications that bias estimates of the relative explosion rates for Type IIb and Ib objects, and that important information about a progenitor star's evolutionary state and mass loss immediately prior to SN explosion can be inferred from timely multi-wavelength observations.
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