Reference Detail

Ref Type

Journal Article

PMID

(28425916)

Authors

Wang HQ, Halilovic E, Li X, Liang J, Cao Y, Rakiec DP, Ruddy DA, Jeay S, Wuerthner JU, Timple N, Kasibhatla S, Li N, Williams JA, Sellers WR, Huang A, Li F

Title

Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
eLife	6		2017 Apr 20		Elife

URL

Abstract Text

The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end, we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53 wild-type neuroblastoma with ALK aberrations.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK R1275Q TP53 wild-type	neuroblastoma	sensitive	Ceritinib + CGM097	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Zykadia (ceritinib) and CGM097 inhibited Alk signaling and resulted in synergistic inhibition of proliferation in a TP53 wild-type neuroblastoma cell line harboring ALK R1275Q in culture and induced tumor regression in a cell line xenograft model (PMID: 28425916).	28425916
ALK amp TP53 wild-type	neuroblastoma	sensitive	Ceritinib + CGM097	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Zykadia (ceritinib) and CGM097 inhibited Alk signaling and resulted in synergistic inhibition of proliferation in a TP53 wild-type, ALK-amplified neuroblastoma cell line in culture and induced tumor regression in a cell line xenograft model (PMID: 28425916).	28425916
ALK F1174L TP53 wild-type	neuroblastoma	sensitive	Ceritinib + CGM097	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Zykadia (ceritinib) and CGM097 inhibited Alk signaling and resulted in synergistic inhibition of proliferation in a TP53 wild-type neuroblastoma cell line harboring ALK F1174L in culture and induced tumor regression in a cell line xenograft model (PMID: 28425916).	28425916