Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Tumor genome sequencing reveals frequent loss-of-function alterations in cancer, presenting challenges for direct therapeutic targeting.
• The synthetic lethality (SL) approach offers a strategy to selectively eliminate cancer cells by exploiting these genetic alterations.
• EPHB6 receptor tyrosine kinase exhibits anti-malignant properties and is downregulated in various cancers, making it a potential target for SL-based therapies.

Purpose of the Study:

• To identify synthetic lethal partners of EPHB6 in triple-negative breast cancer (TNBC) using a genome-wide screen.
• To investigate the therapeutic potential of targeting the identified SL interaction with small molecule inhibitors.
• To evaluate the efficacy of this approach in preclinical TNBC models.

Main Methods:

• Genome-wide synthetic lethality screen in TNBC cells.
• Expression and interaction network analyses to identify SL partners.
• Validation of EPHB6 and SRC kinase as an SL pair.
• Treatment of TNBC xenografts with SRC inhibitors (SU6656 and KX2-391).

Main Results:

• SRC kinase was identified as a synthetic lethal partner of EPHB6 in triple-negative breast cancer cells.
• The identified SL interaction is targetable by small molecule SRC inhibitors, SU6656 and KX2-391.
• Treatment with SRC inhibitors demonstrated improved elimination of human TNBC tumors in a xenograft model.

Conclusions:

• EPHB6 deficiency in TNBC creates a vulnerability that can be exploited through SRC kinase inhibition via synthetic lethality.
• Small molecule SRC inhibitors show potential for personalized treatment of EPHB6-deficient TNBC, an aggressive malignancy with limited targeted therapies.
• These findings provide a proof-of-principle for targeting EPHB6 downregulation in multiple malignancies using the SL approach with small molecule inhibitors.