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

Although small cell lung cancer (SCLC) is clinically heterogeneous, treatment is similar for all SCLC patients and in general lacks sustained efficacy. Gay and colleagues used molecular profiling to identify four SCLC subtypes based primarily on expression of three pivotal transcription factors ASCL1, NEUROD1, and POU2F3 (SCLC-A, N, and P, respectively). The fourth subtype, SCLC-I, exhibited decreased expression of these three biomarkers and was characterized by high levels of inflammation. SCLC-A and SCLC-N subtypes, comprising 67% and 74% of all cases in two published SCLC datasets, represented the neuroendocrine proportion of SCLC, while less abundant SCLC-P and SCLC-I subtypes exhibited non-neuroendocrine features. Prognoses differed among each subtype, with distinct responses to therapeutics. SCLC-I appeared most sensitive to the combination of cisplatin and anti-PD-L1, while the other subtypes were relatively sensitive to specific targeted agents. Subtype intratumoral switching from SCLC-A to SCLC-I was also observed upon treatment with cisplatin, concomitant with therapy resistance.Expert Commentary: The stratification of SCLC tumors into distinct subtypes will allow for subtype-specific therapies, improving the outcome of patients.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 2021;39:346-60.e7. DOI: 10.1016/j.ccell.2020.12.014.Patients with cancer metastasis to the brain show poor survival, with limited therapeutic options. Antibodies targeting human epidermal growth factor 2 (HER2) have increased survival of patients with HER2-positive breast cancer. However, patients with brain metastasis escape anti-HER2 therapy due to the blood brain barrier and a resistant tumor microenvironment. The availability of nutrients fluctuates among tissues, and metabolic adjustments necessary for breast cancer metastasis present possibilities for treatment. Ferraro and colleagues analyzed differences in metabolism between breast tumors localized to the brain versus mammary fat pad. The synthesis of fatty acids was higher when tumors grew in the brain. This pattern was due to lower levels of lipids in the brain compared with other tissues, leading to addiction to fatty acid synthesis for brain metastasis growth. Genetic or pharmacological inhibition of fatty acid synthase led to decreased numbers of HER2-positive tumor cells in the brain.Expert Commentary: The site of metastasis opens possibilities for treatment due to variation in nutrient levels.Ferraro GB, Ali A, Luengo A., Kodack DP, Deik A, Abbott KL, et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer 2021;414-8. DOI: 10.1038/s43018-021-00183-y.Competition for glucose between cancer cells and immune cells can negatively impact antitumor T-cell responses. Zappasodi and colleagues showed that regulatory T cells (Treg) functioned best in glucose-restricted tumors, losing immunosuppressive activity in the presence of glucose. The widely observed anti-correlation between tumor glycolytic activity and immune cell infiltration was noticeably decoupled by anti-CTLA4 checkpoint blockade immunotherapy (CBI). To examine roles for glycolysis, the authors investigated tumor cells deficient for the LDHA enzyme, which slowed glycolysis by preventing pyruvate metabolism. Anti-CTLA4 CBI only significantly suppressed growth of glycolysis-deficient tumors, in which Tregs showed increased IFNγ and TNF production and reduced immunosuppression. As anti-CTLA4 functions as a CD28 agonist and CD28 activity is known to drive glycolysis in T cells by increasing glucose transport, the authors showed that anti-CTLA4 increased glucose uptake in Tregs. Finally, increased glycolysis in Tregs was necessary for CBI-mediated disruption of their immunosuppressive behavior.Expert Commentary: Anti-CTLA4 checkpoint blockade enforces glycolysis in Tregs, disrupting their immunosuppressive activity in tumors when glucose availability is unrestricted.Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 2021; 591:652–8.PD-L1 tumor-intrinsic functions are poorly understood, and it is unclear whether these functions are needed for tumorigenesis or therapeutic response. Chen and colleagues found that PD-L1 signaling induces the epithelial-to-mesenchymal transition and tumor progression through inhibition of the PTP1B/p38-MAPK/GSK3β pathway, leading to increased SNAIL protein stability. PD-L1 was required for a mesenchymal phenotype as well as survival and anchorage-independent growth in vitro. PD-L1 inhibition decreased metastasis in vivo, even in immunocompromised mice. While anti-PD-L1 antibodies could inhibit tumor growth in the absence of an intact immune system, targeting both tumor-intrinsic and -extrinsic PD-L1 functions was synergistic.Expert Commentary: This study highlights an underappreciated PD-L1 tumor-intrinsic function, which may play an important role in therapeutic response to anti-PD-L1 agents.Chen C, Li S, Xue J, Qi M, Liu X, Huang Y, et al. PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer. JCI Insight 2021;6:131458. DOI: 10.1172/jci.insight.131458.The lack of effective strategies for preventing cancer cell dissemination and eliminating metastases highlights the need for further elucidation of the molecular underpinnings of metastasis. New insights into the signaling pathways controlling metastasis have been revealed in a recent study by Wang and colleagues. They showed that genetic or pharmacological inhibition of p38-regulated/activated protein kinase (PRAK), a member of the MAPK-activated protein kinase family, suppresses dissemination, but not primary tumor growth, in a number of different cancer models. PRAK promoted HIF1α translation via regulation of mTORC1 activity, and increased HIF1α signaling is critical for PRAK-mediated metastatic colonization. Interestingly, PRAK expression positively correlated with metastasis and survival in human lung and breast cancer datasets.Expert Commentary: Effective treatment of metastatic growth remains a huge clinical challenge, and identification of targetable pathways will be key to developing effective strategies for managing disease spread.Wang Y, Wang W, Wu H, Zhou Y, Qin X, Wang Y, et al. The essential role of PRAK in tumor metastasis and its therapeutic potential. Nat Commun 2021 Mar 19;12:1736. DOI: 10.1038/s41467-021-21993–9.Aberrant Notch activity plays central roles in the maintenance and survival of cancer stem cells (CSC), which facilitate metastasis and resistance to therapy. Disruption of Notch-driven transcription is therefore a goal in oncology, however, attempts to develop Notch pathway-specific drugs have largely failed due to intestinal toxicity from pan-inhibition of Notch family members. Alvarez-Trotta and colleagues reported the discovery of NADI-351, the first potent, Notch1-selective inhibitor, which disrupted Notch1-transcriptional complexes. NADI-351 dramatically attenuated Notch-dependent tumor cell growth in a variety of cancers, demonstrating robust antitumor activity without inducing intestinal toxicity in mouse models. NADI-351 selectively ablated the CSC population by inhibiting Notch1-directed transcription.Expert Commentary: NADI-351 is an orally available, potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity. The study provides compelling evidence that selective inhibition of Notch1 transcriptional complexes can profoundly arrest tumor growth while avoiding intestinal toxicity through specific depletion of the CSC populations. NADI-351 has promise in translation to the clinic for Notch-dependent cancers.Alvarez-Trotta A, Guerrant W, Astudillo L, Lahiry M, Diluvio G, Shersher E, et al. Pharmacological disruption of the Notch1 transcriptional complex inhibits tumor growth by selectively targeting cancer stem cells. Cancer Research; Published OnlineFirst April 5, 2021; DOI: 10.1158/0008-5472.CAN-20-3611.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.