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Ref Type

Journal Article

PMID

(26577700)

Authors

Herkert B, Kauffmann A, Mollé S, Schnell C, Ferrat T, Voshol H, Juengert J, Erasimus H, Marszalek G, Kazic-Legueux M, Billy E, Ruddy D, Stump M, Guthy D, Ristov M, Calkins K, Maira SM, Sellers WR, Hofmann F, Hall MN, Brachmann SM

Title

Maximizing the Efficacy of MAPK-Targeted Treatment in PTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	2	2016 Jan 15	390-402	Cancer Res

URL

Abstract Text

The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAF(MUT)) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTEN(LOF)) occurs in approximately 40% of BRAF(MUT) melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTEN(LOF)/BRAF(MUT) melanoma. Large-scale compound sensitivity profiling revealed that PTEN(LOF) melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R-PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTEN(LOF)/BRAF(MUT) melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTEN(LOF)/BRAF(MUT) melanoma patients to achieve maximal response.

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Showing 1 to 34 of 34 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF mut PTEN inact mut	melanoma	sensitive	Alpelisib + Encorafenib + GSK2636771	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of GSK2636771, Encorafenib (LGX818), and Alpelisib (BYL719) efficiently inhibited tumor growth in xenograft models of a human melanoma cell line harboring BRAF mutations and PTEN inactivating mutations (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	GSK2636771 + unspecified IGF-1R antibody	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination treatment consisting of GSK2636771 and a figitumumab-like antibody inhibited tumor growth in xenograft models of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Encorafenib + GSK2636771 + unspecified IGF-1R antibody	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination treatment consisting of GSK2636771, Encorafenib (LGX818), and a figitumumab-like antibody inhibited tumor growth in xenograft models of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Alpelisib + GSK2636771	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of GSK2636771 and Alpelisib (BYL719) synergized to inhibit proliferation of human melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture, and inhibited tumor growth in xenograft models of one cell line harboring these mutations (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Alpelisib + AZD6482 + Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, combination treatment consisting of AZD6482, Binimetinib (MEK162), and Alpelisib (BYL719) efficiently induced apoptosis in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482 + Binimetinib + NVP-AEW541	Preclinical	Actionable	In a preclinical study, combination treatment consists of AZD6482, Binimetinib (MEK162), and NVP-AEW541 efficiently induced apoptosis in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Alpelisib + AZD6482 + Binimetinib + Encorafenib	Preclinical	Actionable	In a preclinical study, combination treatment consisting of AZD6482, Binimetinib (MEK162), Encorafenib (LGX818), and Alpelisib (BYL719) efficiently induced apoptosis in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482 + Binimetinib + Encorafenib + NVP-AEW541	Preclinical	Actionable	In a preclinical study, combination treatment consists of AZD6482, Binimetinib (MEK162), Encorafenib (LGX818), and NVP-AEW541 efficiently induced apoptosis in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	TGX-221	Preclinical	Actionable	In a preclincal study, TGX-221 inhibited Akt activation and proliferation in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482 + Encorafenib	Preclinical	Actionable	In a preclinical study, AZD6482 and Encorafenib (LGX818) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Alpelisib + AZD6482	Preclinical	Actionable	In a preclinical study, AZD6482 and Alpelisib (BYL719) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Encorafenib + GSK2636771	Preclinical	Actionable	In a preclinical study, GSK2636771 and Encorafenib (LGX818) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Alpelisib + AZD6482 + Encorafenib	Preclinical	Actionable	In a preclinical study, combination treatment consisting of AZD6482, Encorafenib (LGX818), and Alpelisib (BYL719) efficiently induced apoptosis in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482 + Binimetinib	Preclinical	Actionable	In a preclinical study, AZD6482 and Binimetinib (MEK162) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482	Preclinical	Actionable	In a preclincal study, AZD6482 inhibited Akt activation and proliferation in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	no benefit	Alpelisib + Binimetinib	Preclinical	Actionable	In a preclinical study, Alpelisib (BYL719) and Binimetinib (MEK162) combination treatment did not enhance growth inhibition compared to single agent in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	no benefit	Alpelisib + NVP-AEW541	Preclinical	Actionable	In a preclinical study, Alpelisib (BYL719) and NVP-AEW541 combination treatment did not enhance growth inhibition compared to single agent in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482 + NVP-AEW541	Preclinical	Actionable	In a preclinical study, AZD6482 and NVP-AEW541 synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	decreased response	Alpelisib	Preclinical	Actionable	In a preclincal study, melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations were less sensitive to Alpelisib (BYL719)-induced growth inhibition in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Encorafenib + Pictilisib	Preclinical	Actionable	In a preclinical study, Pictilisib (GDC-0941) and Encorafenib (LGX818) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	GSK2636771 + NVP-AEW541	Preclinical	Actionable	In a preclinical study, GSK2636771 and NVP-AEW541 synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	no benefit	Alpelisib + Encorafenib	Preclinical	Actionable	In a preclinical study, Alpelisib (BYL719) and Encorafenib (LGX818) combination treatment did not enhance growth inhibition in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Binimetinib + GSK2636771	Preclinical	Actionable	In a preclinical study, GSK2636771 and Binimetinib (MEK162) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	AZD6482 + Encorafenib + NVP-AEW541	Preclinical	Actionable	In a preclinical study, combination treatment consists of AZD6482, Encorafenib (LGX818), and NVP-AEW541 efficiently induced apoptosis in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Pictilisib	Preclinical	Actionable	In a preclincal study, Pictilisib (GDC-0941) inhibited Akt activation and proliferation in melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	NVP-AEW541 + Pictilisib	Preclinical	Actionable	In a preclinical study, Pictilisib (GDC-0941) and NVP-AEW541 synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Encorafenib + unspecified IGF-1R antibody	Preclinical	Actionable	In a preclinical study, combination treatment consists of Encorafenib (LGX818) and a figitumumab-like antibody inhibited tumor growth in xenograft models of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations (PMID: 26577700).	26577700
BRAF mut PTEN inact mut	melanoma	sensitive	Binimetinib + Pictilisib	Preclinical	Actionable	In a preclinical study, Pictilisib (GDC-0941) and Binimetinib (MEK162) synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations and PTEN inactivating mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN wild-type	melanoma	no benefit	AZD6482 + Binimetinib	Preclinical	Actionable	In a preclinical study, AZD6482 and Binimetinib (MEK162) combination treatment did not enhance growth inhibition compared to single agent in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN wild-type	melanoma	no benefit	GSK2636771 + NVP-AEW541	Preclinical	Actionable	In a preclinical study, GSK2636771 and NVP-AEW541 combination treatment did not enhance growth inhibition compared to single agent in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN wild-type	melanoma	no benefit	AZD6482 + Encorafenib	Preclinical	Actionable	In a preclinical study, AZD6482 and Encorafenib (LGX818) combination treatment did not enhance growth inhibition compared to single agent in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN wild-type	melanoma	no benefit	AZD6482 + NVP-AEW541	Preclinical	Actionable	In a preclinical study, AZD6482 and NVP-AEW541 combination treatment did not enhance growth inhibition compared to single agent in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN wild-type	melanoma	no benefit	Encorafenib + GSK2636771	Preclinical	Actionable	In a preclinical study, GSK2636771 and Encorafenib (LGX818) combination treatment did not enhance growth inhibition compared to single agent in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture (PMID: 26577700).	26577700
BRAF mut PTEN wild-type	melanoma	no benefit	Binimetinib + GSK2636771	Preclinical	Actionable	In a preclinical study, GSK2636771 and Binimetinib (MEK162) combination treatment did not enhance growth inhibition compared to single agent in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture (PMID: 26577700).	26577700

Showing 1 to 34 of 34 entries

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