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| Ref Type | Journal Article | ||||||||||||
| PMID | (26137449) | ||||||||||||
| Authors | Sweetlove M, Wrightson E, Kolekar S, Rewcastle GW, Baguley BC, Shepherd PR, Jamieson SM | ||||||||||||
| Title | Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth. | ||||||||||||
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| Abstract Text | BRAF and MEK inhibitors have improved outcomes for patients with BRAF-mutant melanoma, but their efficacy is limited by both intrinsic and acquired resistances. Activation of the PI3K pathway can mediate resistance to these agents, providing a strong rationale for combination therapy in melanoma. Here, a panel of nine low-passage human metastatic melanoma cell lines with BRAF mutations was tested in cell proliferation and protein expression assays for sensitivity to inhibitors of MEK (selumetinib) and BRAF (vemurafenib) as single agents and in combination with inhibitors of pan-PI3K (ZSTK474), pan-PI3K/mTOR (BEZ235), individual PI3K isoforms (p110α, A66; p110β, TGX-221; p110γ, AS-252424; p110δ, idelalisib), or mTORC1/2 (KU-0063794). Selumetinib and vemurafenib potently inhibited cell proliferation in all cell lines, especially in those that expressed low levels of phosphorylated AKT (pAKT). ZSTK474 and BEZ235 also inhibited cell proliferation in all cell lines and enhanced the antitumor activity of selumetinib and vemurafenib in the majority of lines by either interacting synergistically or additively to increase potency or by inducing cytotoxicity by significantly increasing the magnitude of cell growth inhibition. Furthermore, ZSTK474 or BEZ235 combined with selumetinib to produce robust inhibition of pERK, pAKT, and pS6 expression and synergistic inhibition of NZM20 tumor growth. The inhibitors of individual PI3K isoforms or mTORC1/2 were less effective at inhibiting cell proliferation either as single agents or in combination with selumetinib or vemurafenib, although KU-0063794 synergistically interacted with vemurafenib and increased the magnitude of cell growth inhibition with selumetinib or vemurafenib in certain cell lines. Overall, these results suggest that the sensitivity of BRAF-mutant melanoma cells to BRAF or MEK inhibitors is at least partly mediated by activation of the PI3K pathway and can be enhanced by combined inhibition of the BRAF/MEK and PI3K/mTOR signaling pathways. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| BRAF V600E/K PIK3CA wild-type | melanoma | sensitive | Vemurafenib + ZSTK474 | Preclinical | Actionable | In a preclinical study, ZSTK474 and Zelboraf (vemurafenib) worked synergistically to inhibit proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | sensitive | Selumetinib + ZSTK474 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Selumetinib (AZD6244) and ZSTK474 combination treatment inhibited proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture, and synergistically inhibited tumor growth in cell line xenograft models (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | sensitive | Dactolisib + Selumetinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Koselugo (selumetinib) and BEZ235 combination treatment inhibited proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture, and synergistically inhibited tumor growth in cell line xenograft models (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | no benefit | TGX-221 | Preclinical | Actionable | In a preclinical study, TGX-221 did not inhibit proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | no benefit | A66 | Preclinical | Actionable | In a preclinical study, A66 did not inhibit proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | sensitive | Selumetinib + Vemurafenib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) and Zelboraf (vemurafenib) worked synergistically to inhibit proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | sensitive | Dactolisib + Vemurafenib | Preclinical | Actionable | In a preclinical study, BEZ235 and Zelboraf (vemurafenib) worked synergistically to inhibit proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture (PMID: 26137449). | 26137449 |
| BRAF V600E/K PIK3CA wild-type | melanoma | no benefit | Idelalisib | Preclinical | Actionable | In a preclinical study, Zydelig (idelalisib) did not inhibit proliferation of melanoma cell lines harboring BRAF V600E/K and wild-type PIK3CA in culture (PMID: 26137449). | 26137449 |