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. 2022 May 19;14(10):2504. doi: 10.3390/cancers14102504

Figure 4.

Figure 4

In this figure, PARPis and anti-VEGF/VEGFRi cooperate to induce HRD. The hypoxia-inducible factor (HIF1) increases VEGF expression, which interacts with neuropilins (NRPs), and VEGF/NRP signaling promotes homologous recombination (HR) through the Hippo pathway transducers YAP/TAZ, which activate the RAD51 promoter via the transcription factor TEAD. In contrast, hypoxia inhibits RAD51 via transcriptional repressor E2F4/p130 or inhibits BRCA1 by epigenetic silencing, leading to impaired HR. Thus, hypoxia exhibits contradictory actions, inhibition, or activation of HR. In this context, anti-VEGF agents or VEGFR inhibitors (VEGFRis) suppress VEGF/NRP signaling, causing impaired HR, whereas PARPis inhibit BRCA1 and RAD51 expression via increased formation of the transcriptional repressor E2F4/p130, resulting in enhanced HRD. Thus, PARPis and anti-VEGF/VEGFRi can cooperate to elicit the HRD phenotype to achieve additive or synergistic effects.