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SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.

The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ∼90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identified tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces a canonical senescence response in a subset of tumors, while, in others, p53 induces a non-apoptotic form of cell death that culminates in necrosis. We pinpointed the cyclophilin family of peptidyl prolyl cis-trans isomerases as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines that are poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity suppresses SCLC subtype-specific p53-mediated death by limiting p53 transcriptional output without impacting chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC can influence the biological response to p53 restoration, describes a novel mechanism of p53-regulated necrotic cell death, and uncovers new targets for the treatment of this most-recalcitrant tumor type.

Meiosis in female oocytes lacks centrosomes, the microtubule-organizing centers. In Drosophila oocytes, meiotic spindle assembly depends on the chromosomal passenger complex (CPC). To investigate the mechanisms that regulate Aurora B activity, we examined the role of protein phosphatase 2A (PP2A) in Drosophila oocyte meiosis. We found that both forms of PP2A, B55 and B56, antagonize the Aurora B spindle assembly function, suggesting that a balance between Aurora B and PP2A activity maintains the oocyte spindle during meiosis I. PP2A-B56, which has a B subunit encoded by two partially redundant paralogs, wdb and wrd, is also required for maintenance of sister chromatid cohesion, establishment of end-on microtubule attachments, and metaphase I arrest in oocytes. WDB recruitment to the centromeres depends on BUBR1, MEI-S332 and kinetochore protein SPC105R. Although BUBR1 stabilizes microtubule attachments in Drosophila oocytes, it is not required for cohesion maintenance during meiosis I. We propose at least three populations of PP2A-B56 regulate meiosis, two of which depend on SPC105R and a third that is associated with the spindle.

Meiosis in female oocytes lack centrosomes, the major microtubule-organizing center, which makes them especially vulnerable to aneuploidy. In the acentrosomal oocytes ofDrosophila, meiotic spindle assembly depends on the chromosomal passenger complex (CPC). Aurora B is the catalytic component of the CPC while the remaining subunits regulate its localization. Using an inhibitor of Aurora B activity, Binucleine 2, we found that continuous Aurora B activity is required to maintain the oocyte spindle during meiosis I, and this activity is antagonized by phosphatases acting on spindle associated proteins such as kinesins. Protein Phosphatase 2A (PP2A) exists in two varieties, B55 and B56. While both antagonize Aurora B, B55 has only minor roles in meiosis I spindle function. The B56 subunit is encoded by two partially redundant paralogs in theDrosophilagenome,wdbandwrd. Knocking down both paralogs showed that the B56 subunit is critical for maintaining sister chromatid cohesion, establishing end-on microtubule attachments, and the metaphase I arrest in oocytes. We found that WDB recruitment to the centromeres depends on BUBR1, MEI-S332, and kinetochore protein SPC105R. While BUBR1 has been shown previously to stabilize microtubule attachments inDrosophilaoocytes, only SPC105R is required for cohesion maintenance during meiosis I. We propose that SPC105R promotes cohesion maintenance by recruiting two proteins that recruit PP2A, MEI-S332, and the Soronin homolog Dalmatian.