Reference Detail

Ref Type

Journal Article

PMID

(36011019)

Authors

Ku GC, Chapdelaine AG, Ayrapetov MK, Sun G

Title

Identification of Lethal Inhibitors and Inhibitor Combinations for Mono-Driver versus Multi-Driver Triple-Negative Breast Cancer Cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancers	14	16	2022 Aug 20		Cancers (Basel)

URL

Abstract Text

There are no signaling-based targeted therapies for triple-negative breast cancer. The development of targeted cancer therapy relies on identifying oncogenic signaling drivers, understanding their contributions to oncogenesis and developing inhibitors to block such drivers. In this study, we determine that DU-4475 is a mono-driver cancer cell line relying on BRAF and the mitogen-activated protein kinase pathway for viability and proliferation. It is fully and lethally inhibited by BRAF or Mek inhibitors at low nM concentrations, but it is resistant to inhibitors targeting other signaling pathways. The inhibitory lethality caused by blocking Mek or BRAF is through apoptosis. In contrast, MDA-MB-231 is a multi-driver triple-negative breast cancer cell line dependent on both Src and the KRAS-activated mitogen-activated kinase pathway for proliferation and viability. Blocking each pathway alone only partially inhibits cell proliferation without killing them, but the combination of dasatinib, an Src inhibitor, and trametinib, a Mek inhibitor, achieves synthetic lethality. The combination is highly potent, with an IC50 of 8.2 nM each, and strikingly synergistic, with a combination index of less than 0.003 for 70% inhibition. The synthetic lethality of the drug combination is achieved by apoptosis. These results reveal a crucial difference between mono-driver and multi-driver cancer cells and suggest that pharmacological synthetic lethality may provide a basis for effectively inhibiting multi-driver cancers.

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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
BRAF V600E	triple-receptor negative breast cancer	sensitive	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mektovi (binimetinib) treatment inhibited Mapk signaling and viability in a triple-negative breast cancer cell line harboring BRAF V600E in culture (PMID: 36011019).	36011019
BRAF V600E	triple-receptor negative breast cancer	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) treatment inhibited Mapk signaling and viability in a triple-negative breast cancer cell line harboring BRAF V600E in culture (PMID: 36011019).	36011019
BRAF V600E	triple-receptor negative breast cancer	sensitive	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment inhibited Mapk signaling and viability in a triple-negative breast cancer cell line harboring BRAF V600E in culture (PMID: 36011019).	36011019