Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy

Abstract

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin–FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.

Bioinformatics analysis of microarray profiling identifies the mechanism of focal adhesion kinase signalling pathway in proliferation and apoptosis of breast cancer cells modulated by green tea polyphenol epigallocatechin 3-gallate

“…[41] FAK gene activation may exert important effects on cell growth and intracellular signal transduction pathways perturbed in response to certain neural peptides or to cell interactions with the extracellular matrix. Accumulating researches demonstrated that inhibition of FAK signalling contributed to suppressing cellular events in various types of cancers including melanomas, [42] ovarian cancer, [43] non-small-cell lung cancer [44] and breast cancer. [45] Our network analysis implicated several pathways including FAK signalling pathway through which EGCG might prevent breast cancer progression, involving cell proliferation and apoptosis.…”

The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation

“…A central mediator of adhesion-dependent signaling, the role of FAK in mechanotransduction is regarded as being less in the generation of cellular tension and more in the transduction of signals downstream of mechanical cell-matrix interactions [65][66][67] . Nonetheless, its demonstrated importance in both functional mechanical signaling [68][69][70][71] and in the biology of EOC [72][73][74][75][76][77] prompted us to assess the effect of FAK inhibition on the EOC mechano-response. Unlike blebbistatin and fasudil, treatment of SKOV3 cells with PF-271 (also known as PF-562271), a potent and highly selective inhibitor of FAK, had no significant effect on cellular traction force ( Figure 8C and D) or stress fiber and phospho-MLC architecture ( Figure 8G and I), but significantly reduced phospho-FAK intensity while preserving or slightly enhancing focal adhesion size and aspect ratio ( Figure 8E and F), consistent with FAK's role in focal adhesion turnover 78 .…”

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

“…In ovarian and prostate carcinoma mouse tumor models, FAK inhibition (VS-6063, defactinib) enhanced taxane-mediated tumor apoptosis (Kang, Hu et al, 2013, Lin, Lee et al, 2018. Additionally, inhibitors of FAK and Myc exhibit combinatorial activity in promoting HGSOC apoptosis in vitro (Xu, Lefringhouse et al, 2017). It remains uncertain whether gains in 8q24 encompassing PTK2 are associated with specific HGSOC cell phenotypes or responses to therapy, as determinants of FAK pathway dependence in tumors remain unknown.…”