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

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.

The intrinsically kinase-inactive EPHB6 receptor predisposes cancer cells to DR5-induced apoptosis by promoting mitochondrial fragmentation

“…Our previous work shows that EPHB6 is synthetic lethal with Src, and TNBC cells and tumours with EPHB6 deficiency are effectively eliminated by Src-inhibiting compounds [37]. Our current findings predict that these same tumour cells will be resistant to DR5 activation because they have relatively low levels of phosphorylated DRP1 and maintain a robust, reticular mitochondrial network.…”

“…The results of our past studies [37] and those presented herein emphasize that whether TNBC tumours express EPHB6 should be a serious consideration with respect to choosing the most efficient therapeutic treatment options. Our previous work shows that EPHB6 is synthetic lethal with Src, and TNBC cells and tumours with EPHB6 deficiency are effectively eliminated by Src-inhibiting compounds [37].…”

“…Both EPHB6 silencing in BT-20 and rescue of EPHB6 expression in MDA-MB-231 cells were described in detail in our earlier publications [29, 37]. EPHB6-expressing and EPHB6-deficient cells from both TNBC lines were stimulated with an activating anti-DR5 antibody, and cell survival was monitored using resazurin staining or the MTT assay.…”

“…Taken together, these findings provide strong support for an entirely novel model, where EPHB6 augments the pro-apoptotic effect of DR5 on TNBC cells by activating ERK2-DRP1 signaling, which in turn induces fragmentation of the mitochondrial network. Our model also provides a rational explanation for why in multiple cancer types, malignant tumours tend to reduce EPHB6 expression [37], since a decrease in EPHB6 levels should improve survival of cancer cells by protecting them from immunoelimination mediated by DR5 activation [43–45]. …”

Therapeutic relevance of the protein phosphatase 2A in cancer

“…Continued efforts in tumor sequencing have greatly facilitated the identification of the molecular alterations that provide novel opportunities to develop customized precision medicine [ 1 ]. However, the depth of molecular alterations observed within the malignancies that manifest as tumor heterogeneity represent a major roadblock, as the genetic diversity within a single tumor may lead to differential response of the tumors to targeted therapies and subsequent treatment failure [ 2 , 3 ].…”