In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 634-634
Abstract:
V600EB-RAF mutation is found in 50-60% of melanomas, and its in-human “druggability” has recently been demonstrated using the novel agent PLX4032, which can achieve an unprecedented ∼80% on-target, anti-melanoma response rate. Acquired resistance to PLX4032, however, has been observed in the majority of patients. We have shown previously that melanoma tumors in patients and cell lines in vitro acquire resistance to PLX4032 not by developing secondary mutations in V600EB-RAF but instead by upregulating PDGFRβ (showing MEK inhibitor insensitivity) or N-RAS (showing MEK inhibitor sensitivity). Here we used distinct subsets of melanoma cell lines (resistance derived in vitro) and short-term cultures (resistance derived in vivo) with hitherto characterized mechanisms of acquired resistance to PLX4032 to define the optimal combination of molecular target inhibition necessary to achieve efficient growth inhibition and cytotoxicity. We focused on a set of molecular targets downstream of overexpressed PDGFRβ or mutant N-RAS in each subset and used specific small molecule inhibitors, singly or in combination, to correlate growth inhibitory responses with p-ERK, p-AKT, p-p70S6K levels and apoptotic responses. We found that single inhibitor treatment led to functionally significant compensatory activation or rebound activities, consistent with dynamic network connectivity at key nodes of signaling. In PDGFRβ-upregulated, PLX4032-resistant melanoma cell lines, combined B-RAF, PI3K and TORC1/2 inhibition led to the strongest synergistic growth inhibitory and cytotoxic responses. In N-RAS-upregulated, PLX4032-resistant cell lines, either MEK or dual TORC1/2 inhibition sufficed to yield significant growth inhibition, and combined MEK and TORC1/2 inhibition did not synergize in growth inhibitory or cytotoxic responses. Together, these observations could serve to rationally guide animal model studies and urgently needed clinical testing in pre-identified subsets of patients relapsing on V600EB-RAF inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 634. doi:10.1158/1538-7445.AM2011-634
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-634
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
