Abstract
Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.
Highlights
The establishment of the estrogen receptor and human epidermal growth factor receptor-2 (HER2) as therapeutically relevant targets marked the development of genotype-directed treatment for breast cancer patients
As transcriptional regulation of EPHB6 was suggested to be controlled by promoter methylation in breast cancer cell lines [16], we analyzed human cancer methylome data and found that EPHB6 is methylated in the promoter region in several malignancies, including breast, colon, lung and prostate tumors (Figure 1B)
The relevance of this finding is further supported by recent unfortunate observations, revealing that SRC is frequently overexpressed in cancer, in some clinical trials randomly applied SRC inhibition produced limited positive effects on cancer patients [26]
Summary
The establishment of the estrogen receptor and human epidermal growth factor receptor-2 (HER2) as therapeutically relevant targets marked the development of genotype-directed treatment for breast cancer patients. Development of mechanisms or tools to efficiently utilize these loss-of-function alterations for therapeutic purposes would dramatically expand our options in treatment personalization In this context, the identification of synthetic lethal (SL) interactions, where suppression of one gene causes lethality only when another gene is inactivated [2, 3], provides a unique opportunity to target these loss-of-function genetic defects. EPHB6 lacks catalytic activity due to several intrinsic alterations in the sequence of its kinase domain [4] and in contrast to other Eph receptors [5–7 ], EPHB6 is often downregulated in various malignancies, including metastatic lung cancer [8], melanoma [9], prostate cancer [10], ovarian carcinoma [11], gastric cancer [12], aggressive neuroblastoma [13, 14], and invasive breast cancer cell lines [15, 16] This agrees well with the previously reported EPHB6 ability to suppress metastasis in non-small cell lung cancer [17] and melanoma [18], and our own findings that EPHB6 actively reduces breast cancer invasiveness [19]. These observations indicate that EPHB6 receptor deficiency may potentially be targeted by using the SL approach to further personalize cancer therapy and improve treatment in multiple malignancies
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