Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability
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Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair
FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase 3 beta (GSK3β) and the homologous recombination DNA repair (HRR) pathway are synthetic lethal with FHIT loss in lung cancer. Pharmacological inhibition or siRNA depletion of GSK3β selectively suppressed the growth of FHIT-deficient lung cancer tumors in vitro and in animal models. We further showed that FHIT inactivation leads to the activation of DNA damage repair pathways, including the HRR and NHEJ pathways, in lung cancer cells. Conversely, FHIT-deficient cells are highly dependent on HRR for survival under DNA damage stress. The inhibition of GSK3β in FHIT-deficient cells suppressed the ATR/BRCA1/RAD51 axis in HRR signaling via two distinct pathways and suppressed DNA double-strand break repair, leading to the accumulation of DNA damage and apoptosis. Small molecule inhibitors of HRR, but not NHEJ or PARP, induced synthetic lethality in FHIT-deficient lung cancer cells. The findings of this study suggest that the GSK3β and HRR pathways are potential drug targets in lung cancer patients with FHIT loss.
Mitochondrial priming and response to BH3 mimetics in “one-two punch” senogenic-senolytic strategies
A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state—the proximity to the apoptotic threshold—and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of “one-two punch” senogenic-senolytic strategies.
SETD1A-dependent EME1 transcription drives PARPi sensitivity in HR deficient tumour cells
Cells deficient in DNA repair factors breast cancer susceptibility 1/2 (BRCA1/2) or ataxia-telangiectasia mutated (ATM) are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Building on our previous findings, we asked how the lysine methyltransferase SETD1A contributed to PARP inhibitor-mediated cell death in these contexts and determined the mechanisms responsible.
Reduced reproductive potential in young healthy women with hereditary breast and/or ovarian cancer syndrome
Young, healthy women carrying a pathogenic or likely pathogenic variant (P/LPV) in genes configuring the hereditary breast and/or ovarian cancer (HBOC) syndrome face several non-oncological issues. Among these, the implications on fertility are not yet entirely understood.
The transcriptomic architecture of common cancers reflects synthetic lethal interactions
To maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted by synthetic lethality. However, despite the large-scale identification of synthetic lethal effects in preclinical models, evidence that these operate clinically is limited. This impedes the application of synthetic lethal approaches. By integrating molecular profiling data from >9,000 cancers with synthetic lethal screens, we show that transcriptomic buffering of tumor suppressor gene (TSG) loss by hyperexpression of synthetic lethal partners is a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic buffering is also notable in cancers that phenocopy TSG loss, such as BRCAness cancers, where expression of BRCA1/2 synthetic lethal genes correlates with clinical outcome. Synthetic lethal genes that exhibit transcriptomic buffering also represent more robust synthetic lethal effects. These observations have implications for understanding how tumor cells tolerate TSG loss, in part explain transcriptomic architectures in cancer and provide insight into target selection.
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