Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition

Abstract

Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-017-3401-y) contains supplementary material, which is available to authorized users.

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

“…BAP1 modulates double‐strand DNA damage repair . Cells with BAP1 mutations are more sensitive to both radiation and treatment with olaparib, a PARP inhibitor . There is an ongoing phase 2 study of olaparib in mesothelioma (ClinicalTrials.gov identifier NCT03531840).…”

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

“…Among the NCI patients with mesothelioma with inherited BAP1 mutations, all tumors harbored additional, somatic mutations likely leading to complete loss of BAP1 function. Cell lines with these features are sensitive to PARP inhibitors (28,29), suggesting that these primary tumors might also be particularly vulnerable to PARP inhibitors (43). Whether patients with mesothelioma with inherited mutations in BAP1 or related DNA repair genes would benefit from PARP inhibitor therapy is now an open question (15).…”

“…synthetic lethality of alternate DNA repair pathways (25)(26)(27). Cell lines with loss of function of BAP1 are also sensitive to PARP inhibitors (28)(29)(30).…”

Genomic Instability in Kidney Cancer: Etiologies and Treatment Opportunities

“…Other driver mutations in RCC also have been shown to lead to PARP inhibitor sensitivity by way of creating an HRD phenotype. For example, preclinical studies have shown a synthetic lethal relationship between PARP1 and BAP1 with BAP1-deficient cells showing sensitivity to PARP inhibition [32,42], thus clinical trials testing PARP inhibition in BAP1mutant tumors, including mesothelioma [43] and RCC amongst others, are in development ( Table 1). Loss of function mutations in ARID1A occur across a variety of cancers, including ccRCC, and mutations in this gene have been shown to give sensitivity to both PARP [44] inhibition and ATR inhibition [45] in preclinical cancer models, and PARP-inhibitor based clinical trials that select for patients with ARID1A mutations, including patients with ccRCC, are ongoing (e.g.…”