Although mutations in PIK3CA, encoding the insulin-activated phosphoinositide-3-kinase (PI3K), occur commonly in cancer, variable clinical responses to PI3K inhibition suggest an inherent resistance mechanism. Importantly, PI3K inhibition disrupts glucose metabolism in several tissues. Blocking insulin signaling increases glycogen breakdown in the liver and inhibits glucose uptake in tissues, resulting in hyperglycemia. In patients with insulin resistance, hyperglycemia may require interruption of the therapy. Hopkins and colleagues showed in several mouse models that systemic glucose-insulin feedback caused by targeted inhibition of this pathway was sufficient to activate PI3K signaling, even in the presence of PI3K inhibitors. Moreover, feedback could be prevented by dietary or pharmacological approaches, which greatly enhanced the efficacy of these compounds.Expert Commentary: These findings may impact many PI3K inhibitors clinical trials and may provide a way to increase efficacy for patients.Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature; Published online July 4, 2018; doi: 10.1038/s41586-018-0343-4.The von Hippel-Lindau (VHL) gene, encoding a ubiquitin ligase that targets proline hydroxylated substrates, is inactivated commonly in clear cell renal carcinoma (ccRCC). Although HIFα is the best-known substrate of VHL, inhibitors of HIFα exhibit efficacy only against a subset of ccRCC. Zhang and colleagues identify a novel VHL substrate, the transcription factor ZHX2. In the presence of VHL, ZHX2 was prolyl hydroxylated and degraded in a proteasome-dependent manner. Loss of VHL stabilized and enriched ZHX2 in the nucleus. Knockdown of ZHX2 reduced growth of VHL mutant ccRCC in vitro and in vivo. NF-κB was the major ZHX2-regulated signaling pathway. Importantly, a VHL mutant unable to associate with ZHX2 promoted ccRCC growth in a manner attenuated by inhibition of NF-κB.Expert Commentary: ZHX2 represents a novel therapeutic target in VHL mutant ccRCC.Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, et al. VHL substrate transcription factor ZHX2 as an oncogenic driver in clear renal cell carcinoma. Science 2018;361:290–5.Wu and colleagues reveal mechanistic insights connecting diabetes and cancer, revealing that hyperglycemia reduces the activity of TET2. TET2 is a tumor suppressor that converts 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), the first step of DNA demethylation. They show TET2 as a direct target of the energy-sensing kinase, AMPK. Phosphorylation of TET2 by AMPK stabilized TET2 protein, boosting generation of 5hmC. Diabetic patients have reduced AMPK activity, TET2 stability, and 5hmC levels. TET2+ tumors grow faster in diabetics, compared to normal glycemic mice, but tumor growth can be stunted by pharmacologic activation of AMPK.Expert Commentary: Diabetic hyperglycemia promotes cancer progression by impeding AMPK-mediated stabilization of TET2. The tumor suppressive activity of TET2 can be enhanced by treatment with the AMPK agonist metformin.Wu, D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 2018;559:637–41.Somatic mutations in the isocitrate dehydrogenase 2 (IDH2) gene contribute to acute myeloid leukemia (AML) pathogenesis. Intlekofer and colleagues sequenced bone marrow aspirates from patients with IDH2-mutant leukemia who acquired resistance after an initial robust response to the IDH inhibitor enasidenib. Sampling revealed initial eradication of subclones expressing neomorphic IDH2R140Q mutations, followed by re-emergence along with de novo second-site mutations (IDH2Q316E and IDH2I319M). Long-range PCR demonstrated second-site mutations in trans and not cis. Both de novo mutations mapped to the IDH2 dimeric binding pocket. Expression of either of these mutant alleles alone did not induce production of the neometabolite 2-HG, confirming these were nononcogenic; however, expression of either mutation together with the R140Q mutation in trans in murine models allowed production of 2-HG and resistance to enasidenib. Analysis of additional enasidenib-resistant tumors supported a similar mechanism in IDH1, with disruption of enasidenib binding occurring in cis.Expert Commentary: This study provides a new example of second-site mutations after initial responses to targeted therapy.Intlekofer AM, Shih AH, Wang B, Nazir A, Rustenburg AS, Albanese SK, et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 2018;559:125–9.Poly (ADP-ribose) polymerase (PARP) inhibitors, used for BRCA1- and BRCA2-deficient tumors, target deficiencies in homologous recombination. Zimmermann and colleagues undertook CRISPR screens to identify genes that mediated resistance to the PARP inhibitor olaparib. Loss of all three genes encoding the ribonuclease H2 complex sensitized cells to PARP inhibition. Further CRISPR screens in RNASEH2A knockout cell lines revealed a genetic dependency on PARP1 for PARP inhibitor-induced cytotoxicity. Impaired ribonucleotide excision repair in the ribonuclease H2– deficient cells led to increased genome-embedded nucleotides that were substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions required for cytotoxicity of PARP inhibitors.Expert Commentary: The observation that RNASEH2B is frequently deleted in metastatic prostate cancer and chronic lymphocytic leukemia offers a therapeutic opportunity and expands the possible use of PARP inhibitors to tumors that are proficient in homologous recombination.Zimmermann M, Murina O, Reijns MAM, Agathanggelou A, Challis R, Tarnauskaitè Z, et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 2018;559:285–9.Acute lymphoblastic leukemia (ALL) frequently metastasizes to the central nervous system (CNS). Yao and colleagues found that ALL cells were unable to invade the blood-brain barrier, but rather migrated abluminally in a manner dependent on α6 integrin laminin, utilizing emissary vessels from the bone marrow into the CNS. Inhibition of PI3Kδ, an approved treatment for indolent B-cell lymphomas, decreased expression of α6 integrin and migration to the CNS, extending survival in multiple mouse models of ALL. Correspondingly, inhibition of α6 integrin decreased CNS burden in vivo and high expression of α6 integrin was associated with CNS disease in patients with ALL.Expert Commentary: This study identifies a mechanism for leptomeningeal invasion by ALL and suggests that the use of PI3Kδ inhibitors may be effective to prevent and treat CNS disease.Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature; Published online July 18, 2018; doi: 10.1038/s41586-018-0342-5.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.