PRICKLE4 Underlies IDH mutant Tumors Resistance against PARP Inhibition

Mutations in isocitrate dehydrogenase (IDH) genes render affected gliomas sensitive to PARP inhibition due to epigenetic reprogramming of the DNA damage repair circuits. However, PARPi treated tumor eventually relapse. We report in this study that anti-angiogenetic agent lenvatinib efficiently cooperate with PARPi and the combination therapy induces marked tumor regression and significant extension of survival time. Genomic study with PARPi and lenvatinib treated tumor samples uncovered that PARPi evokes global transcriptome changes that are overall pro-inflammatory, thus inducing tumor angiogenesis. We identified that prickle planar cell polarity protein 4 (Prickle4) as the specific mediator for PARPi induced neovascularization. Suppression of Prickle4 efficiently overcomes PARPi resistance in these tumors. Overall, multimodality therapy combining PARPi and anti-angiogenetic agents represents a feasible treatment that is of excellent potential for clinical applications. Veliparib and lenvatinib together displayed prominent tumor regressive activity that neither of the two administrated alone achieved. We reasoned that this activity may be linked to molecular changes post one drug treatment that render tumor cells sensitive to another, rather than a simple combinatory effect of drugs. It is also possible that the resistent mechanisms that one drug treatment stimulated is overcome by its corresponding blockade agent. And information of these changes can only be broadly captured by genomic studies to elaborate these mechanisms. To determine this, we subjected fresh tumor samples 9 days post treatment regimens to transcriptional profiling with bulk RNA sequencing.