Highlights from Recent Cancer Literature

Abstract

The mammalian/mechanistic target of rapamycin kinase (mTOR) is a core regulator of cell growth, metabolism, and translation, and is commonly dysregulated in brain tumors. Several mTOR inhibitors have been identified, but the multifarious functions of this signaling pathway mean that such inhibitors have substantial side effects. Here, a combinatorial approach was devised to limit the activity of a brain-permeant mTOR inhibitor, RapaLink-1, in tissues outside the brain. Zhang and colleagues found that RapaLink-1 requires the FKBP12 protein for its inhibitory effect in cells and generated brain-impermeant derivatives of a natural ligand of FKBP12, FK506, with the goal of blocking this activity. One derivative, RapaBlock, potently limited RapaLink activity but was brain impermeant; thus, the administration of both compounds allowed mTOR inhibition in the brain while sparing other tissues. Finally, the authors demonstrated that the strategy used in this case may be more broadly applicable to other kinase inhibitors via their chemical coupling to FK506 fragments.Expert Commentary: RapaBlock represents an agent with broad potential to minimize side effects of select kinase inhibitors in brain cancer.Zhang Z, Fan Q, Luo X, Lou K, Weiss WA, Shokat KM. Brain-restricted mTOR inhibition with binary pharmacology. Nature 2022;609:822-29.Numerous mechanisms of checkpoint blockade immunotherapy (CBI) resistance have been uncovered, but whether there are conserved mechanisms across tumor types has not been well established to date. Dubrot and colleagues defined unique and shared mechanisms of resistance to CBI by performing genome-wide pooled CRISPR-based screens across numerous mouse cancer models. Activation of IFN-stimulated pathways represented a shared mechanism of resistance for most models. While activation of the pathway improves CD8+ T-cell recognition by increasing classical MHC-I antigen presentation, activation also promotes resistance by upregulating the inhibitory checkpoint ligand PD-L1. However, the authors found that upregulation of MHC-I itself inhibited CBI by diminishing the activity of natural killer (NK) cells. Furthermore, they found that the nonclassical MHC-I protein Qa-1b (HLA-E in humans) was upregulated in response to IFN signaling and this inhibited CD8+ T cells via binding of inhibitory receptors NKG2A/CD94. In patients with renal cancer and metastatic melanoma, high IFN signatures correlated inversely with efficacy for CBI.Expert Commentary: Upregulation of classical and nonclassical MHC-I molecules in response to CBI promotes cancer resistance to NK and T cells.Dubrot J, Du PP, Lane-Reticker SK, Kessler EA, Muscato AJ, Mehta A, et al. In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer. Nature Immunology; Published online September 23, 2022; doi: 10.1038/s41590-022-01315-x.Cells deficient in BRCA2 undergo DNA double-stranded breaks and chromosomal rearrangements, and activate mitotic DNA synthesis (MiDAS), a form of DNA repair that counteracts potentially lethal chromosome missegregation and nondisjunction. Groelly and colleagues applied high-throughput MiDAS sequencing to map sequences sites where MiDAS occurred in BRCA2-deficient cells. In H1299 and HELA BRCA2 knockdown cells, loss of BRCA2 triggered MIDAS at loci that replicated in early S-phase and were highly transcribed. BRCA2-deficient cells had MiDAS distinct from aphidicolin, an inhibitor of DNA polymerase known to induce MiDAS and cell death. Lastly, RAD52-mediated MiDAS promoted genome integrity in BRCA2-negative cells but combined RAD52 and BRCA2 loss promoted DNA damage, supporting a synthetic lethal interaction between RAD52 and BRCA2.Expert Commentary: This study suggests that loss of the tumor predisposing BRCA2 gene links transcriptionally induced DNA damage with mitotic DNA repair to promote genomic instability, a hallmark of cancer.Groelly FJ, Dagg RA, Petropoulos M, Rossetti GG, Prasad B, Panagopoulos A, et al. Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells. Mol Cell 2022;82:3382-97.e7.MET amplification is an established common driver of resistance in EGFR-mutant non-small cell lung cancer (NSCLC). Patients with EGFR-mutant NSCLC also show poor response to anti-PD-1/PD-L1 immunotherapy. Yoshida and colleagues have now identified that MET amplification activates STING expression in tumor cells. However, despite elevated STING expression, these cells demonstrate impaired T-cell antigen-specific recognition responses due to CD73 upregulation. The folate antimetabolite pemetrexed, used frequently in patients resistant to EGFR-TKIs, increases STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR TKI-resistant cells. However, pemetrexed further induces CD73 expression and enhances basal production of adenosine, creating an immune suppressive tumor microenvironment. Interestingly, pemetrexed coupled with CD73 knockout or a CD73 inhibitor significantly enhanced TCR recognition of a model T-cell antigen and promoted immunogenicity.Expert Commentary:MET amplification upregulates CD73-suppressing tumor cell STING induction and T-cell responsiveness in TKI-resistant, EGFR-mutated lung cancer. Combining CD73 inhibition with folate antimetabolites activates the STING pathway, providing a potential strategy to enhance immunogenicity and to improve treatment.Yoshida R, Saigi M, Tani T, Springer BF, Shibata H, Kitajima S, et al. MET-induced CD73 restrains STING-mediated immunogenicity. Cancer Res2022;82: doi: 10.1158/0008-5472.CAN-22-0770.T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive blood cancer. Prognosis for relapsed T-ALL is poor, with limited targeted therapeutic options. Lymphocyte-specific protein tyrosine kinase (LCK) dependency in T-ALL occurs in a large proportion of patients, and the small molecule inhibitor dasatinib has shown limited promise in slowing leukemic growth. Hu and colleagues used dasatinib as the LCK ligand to develop LCK-targeting proteolysis-targeting chimeric (PROTAC) molecules, therapeutic modalities that harness the ubiquitin-proteasome system to degrade proteins. They developed LCK degraders with efficient proteolysis and cytotoxicity in T-ALL. These PROTACs showed minimal cytotoxicity on normal hemopoiesis. A kinome screen showed selectivity toward LCK, SRC, and ABL kinases. Compared with dasatanib, LCK PROTACs demonstrated more prolonged LCK inhibition and extended survival times in patient-derived xenograft models.Expert Commentary: LCK-based PROTACs show great promise for a precision medicine therapeutic option in T-ALL and other cancers with aberrant kinase signaling.Hu J, Jarusiewicz J, Du Q, Nishiguchi G, Yoshimura S, Panetta JC, et al. Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia. Sci Transl Med 2022;14:eabo5228. doi: 10.1126/scitranslmed.abo5228.Although response to EGFR tyrosine kinase inhibitors (TKI) is quite high, the development of drug tolerance and resistance is inevitable. Nie and colleagues identified acetylcholine as a mediator of drug-tolerant persister cells and subsequent resistance. They demonstrated that acetylcholine and its metabolic enzymes were upregulated in drug-tolerant persister cells after treatment with TKIs and that inhibition of the acetylcholine pathway decreased formation of drug-tolerant persister cells and tumor growth. Furthermore, high baseline plasma acetylcholine or tumor choline acetyltransferase correlated with worse outcomes in patients with EGFR-mutant tumors.Expert Commentary: This study suggests a novel strategy to prevent resistance to inhibitors of EGFR through inhibition of the acetylcholine pathway with darifenacin.Nie M, Chen N, Pang H, Jiang T, Jiang W, Tian P, et al. Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse. The Journal of Clinical Investigation; Published online September 1, 2022; doi: 10.1172/JCI160152.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.