Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

Small cell lung cancer (SCLC) is currently treated as a homogenous cancer, resulting in dismal outcomes. Gay and colleagues characterized four molecularly distinct SCLC subtypes based on transcription factor expression (ASCL1, NEUROD1, and POU2F3). The fourth novel subtype was defined by the presence of a mesenchymal and inflammatory phenotype and absence of transcription factor expression (SCLC-I). SCLC-I patients had the greatest benefit from immunotherapy, while the three other subtypes had improved responses preclinically to PARP, Aurora kinase, or BCL2 inhibitors, respectively. Subtype plasticity was observed during platinum resistance with subtype transdifferentiation to the SCLC-I subtype.Expert Commentary: This study suggests that transcription factor expression subtyping of SCLC may enable precision therapy.Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell; Published online January 5, 2021; DOI: 10.1016/j.ccell.2020.12.014.An antibody directed against integrin αvβ6/8 was shown to sensitize breast cancer cells to cytotoxic T cells and to provide significant survival benefit in mouse models of triple-negative breast cancer (TNBC) in combination with immune checkpoint therapy. Blockade of αvβ6 resulted in release of TGFβ from a latent precursor, and subsequent activation of TGFβ-SOX4-dependent expression of genes in innate and adaptive immune pathways. Targeting SOX4 with the integrin αvβ6/8 antibody inhibited emergence of tumor cells resistant to cytotoxic T cells due to low MHC class I expression.Expert Commentary: With αv blocking antibodies in clinical development, this study identifies a targetable pathway in TNBC, a cancer subtype that is notoriously difficult to treat. It will be of interest to establish if this pathway is conserved in other tumor types.Bagati A, Kumar S, Jiang P, Pyrdol J, Zou AE, Godicelj A, et al. Integrin αvβ6–TGFβ–SOX4 pathway drives immune evasion in triple-negative breast cancer. Cancer Cell 2021;39:54–67.e9. DOI: 10.1016/j.ccell.2020.12.001.Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with small cell lung cancer (SCLC). Zhu and colleagues report lack of surface ligands for the natural killer (NK)-activating receptor NKG2D in both preclinical and clinical samples of neuroendocrine SCLC and neuroblastoma. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Interestingly, HDAC inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype.Expert Commentary: Epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells. This study discovers impairment of an inherent mechanism of recognition of tumor cells by innate immunity in SCLC and neuroblastoma and proposes reactivation to promote immune surveillance.Zhu M, Huang Y, Bender ME, Girard L, Kollipra R, Eglenen-Polat B, et al. Evasion of innate immunity contributes to small cell lung cancer progression and metastasis. Cancer Res 2021;81:1813–26.Endersby and colleagues screened almost 3,000 unique and approved compounds across a panel of patient-derived models for MYC-amplified Group 3 medulloblastoma. Among rare compounds that exhibited activity, they identified the common chemotherapeutic agent gemcitabine, as well as inhibitors of PI3K, HDAC, and CHK1/2 kinase. Although none of the CHK1/2 inhibitors tested was active as monotherapy in vivo, combinatorial therapy of the best-in-class CHK1 inhibitor LY2606368 with either cyclophosphamide or gemcitabine resulted in significant extension of survival across several MYC-amplified Group 3 PDX models. They further confirm in a sporadic transgenic model that LY2606368 crossed the blood brain barrier and attenuated the DNA damage response mediated by chemotherapy. A highly novel aspect of this study was the in vivo validation of this strategy across multiple centers.Expert Commentary: This study elegantly vets a novel compound to enhance the potency of chemotherapy, thus providing a rational approach to treatment of high-risk medulloblastoma (NCT04023669).Endersby R, Whitehouse J, Pribnow A, Kuchibhotla M, Hii H, Carline B, et al. Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma. Sci Transl Med 2021;13:eaba7401. DOI: 10.1126/scitranslmed.aba7401.Although the majority of cancer cells exhibit aneuploidy, it remains unclear how to leverage this vulnerability to identify anticancer drugs. To identify potential liabilities, Cohen-Sharir and colleagues examined the aneuploidy landscape of 1,000 cancer cell lines and correlated this information with genetic and drug screen sensitivity data. Many of their candidates clustered in pathways associated with the spindle assembly checkpoint (SAC). In contrast to their genetic screen results, their analysis of drug screen data showed that highly aneuploid cells were more resistant to a broad range of inhibitors. This apparent discrepancy in response was due to differences in their time of analysis, with highly aneuploid cancer cells being more sensitive to longer term treatment with either molecular genetic or chemical SAC inhibitors. They suggest a model by which highly aneuploid cells initially overcome SAC inhibition more rapidly than near-diploid cells, but that this ultimately results in mitotic defects and cell death.Expert Commentary: This study identifies a therapeutically relevant weakness of aneuploid cancer cells.Cohen-Sharir Y, McFarland JM, Abdusamad M, Marquis C, Bernhard SV, Kazachkova M, et al. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature 2021;590:486–91.Pancreatic adenocarcinoma (PDAC) is a deadly malignancy with poor outcomes despite advances in surgery, radiation, and chemotherapy. Stromal fibrosis activates prosurvival and pro-epithelial-to-mesenchymal transition (EMT) pathways in PDAC. Mueller and colleagues found upregulation of fibrosis, extracellular matrix, and EMT gene signatures in tumors from patients treated with neoadjuvant stereotactic body radiation therapy. Radiation therapy resulted in increased expression of the cell surface protein ADAM10 in tumor cells, leading to cleavage of the transmembrane protein ephrin-B2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased radiation-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation-induced killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrin-B2 in fibroblasts reduced the metastatic potential of tumor cells after radiation therapy.Expert Commentary: This study suggests that targeting the cellular and microenvironmental response to radiation may enhance the efficacy of standard treatments and may promote enhanced therapeutic responses with cutting edge radiation delivery.Mueller AC, Piper M, Goodspeed A, Bhuvane S, Williams JS, Bhatia S, et al. Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer. Cancer Research; Published online February 1, 2021; DOI: 10.1158/0008-5472.CAN-20-3892.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.