The serine/threonine liver kinase B1 (LKB1) is a tumor suppressor and a well-established activator of AMPK kinases involved in cellular meta-bolism. In addition to restricting tumor growth, LKB1 has also been shown to limit the metastatic potential of tumor cells, but it is unclear if this is dependent on AMPK. Pierce and colleagues described a novel function of this kinase by showing that LKB1 regulates chromatin accessibility, mediated via the SIK family of kinases in lung cancer. High levels of the transcription factor SOX17 and increased accessibility of genomic regions that contain SOX motifs correlated with metastatic progression in LKB1-deficient mouse lung adenocarcinomas. Interestingly, some primary lung tumors contained a metastatic-like population of SOX17+ cells, with SOX17 being sufficient to drive epigenetic changes in LKB1-deficient cells that drive metastases.

Expert Commentary: The identification of epigenetic differences in primary tumors and metastatic lesions driven by LKB1 loss highlights the ability of individual genetic alterations to differentially alter cancer phenotypes at different stages of disease progression.

Pierce SE, Granja JM, Corces MR, Brady JJ, Tsai MK, Pierce AB, et al. LKB inactivation modulates chromatin accessibility to drive metastatic progression. Nat Cell Biol 2021;23:915–24.


In response to therapeutics, a subset of cancer cells enters a reversible drug tolerant state through mechanisms that have not been fully described. The majority of “persister cells” remain quiescent, but some are able to proliferate despite the presence of cancer therapeutics, presenting a mechanism by which tumors can obtain drug resistance. Oren and colleagues used a novel barcoding lentiviral system to simultaneously trace the growth and gene expression patterns of persister cell lineages at different time points following treatment with the EGFR inhibitor osmertinib. They showed that cycling and noncycling persister cells arose from different cell lineages, and cycling persister cells exhibited an increased antioxidant program and fatty acid metabolism. Importantly, modulating these programs altered the number of cycling persister cells. Cells with similar properties were found in multiple types of drug-treated tumor cells, mouse models, and patient tumors.

Expert Commentary: The identification of novel biological programs that regulate cycling persister cells, which drive drug resistance in multiple types of cancer, could enable novel ways to prevent such resistance.

Oren Y, Tsabar M, Cuoco M, Amir-Zilberstein L, Cabanos HF, Hütter JC, et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature 2021;596:576–82.


Small cell lung cancer (SCLC) is an aggressive and deadly, with limited effective therapies. However, there is increasing evidence that altered epigenetic remodeling is a key driver of this disease and could present a therapeutic target. Following previous work demonstrating a role for the BAP1/ASXL3/BRD4 epigenetic axis in SCLC, Zhao and colleagues used a genome-wide CRISPR-Cas9 screen to identify paired box protein 9 (PAX9) as a downstream transcriptional target upregulated by this chromatin remodeling complex. PAX9 is a transcription factor, however, the authors observed low occupancy of PAX9 at gene promoters and identified PAX9 was almost exclusively localized to primed enhancers in SCLC. Functionally, PAX9 interacts with components of the nucleosome remodeling and deacetylase (NuRD) complex to restrict expression of tumor suppressor genes, which could be reversed by either genetic depletion of PAX9 or pharmacological HDAC inhibition.

Expert Commentary: This study provides mechanistic insights into the oncogenic function of the PAX9/NuRD complex in human SCLC and suggests reactivation of primed enhancers as a treatment for SCLC expressing high levels of PAX9.

Zhao Z, Szczepanski AP, Tsuboyama N, Abdala-Valencia H, Goo YA, Singer BD, et al. PAX9 determines epigenetic state transition and cell fate in cancer. Cancer Res 2021;81:4696–708.


Despite evidence that pancreatic ductal adenocarcinoma (PDAC) cells express tumor-specific antigens, the use of immunotherapy has been largely ineffective as a treatment option for this disease, suggesting PDAC cells upregulate mechanisms to evade immune detection. Freed-Pastor and colleagues analyzed PDAC whole exome data and found nearly all cancers contain mutationally derived neoantigens predicted to bind MHC class I. However, freshly isolated human PDAC revealed CD8+ T cells with an exhausted phenotype. Additionally, employing an organoid-based transplantation model and an autochthonous model of PDAC, they showed that tumors expressing model neoantigens were either edited (losing neoantigen expression) or progressed while maintaining neoantigen expression. The authors examined immune inhibitory ligand expression in human PDAC and found CD155 to be highly expressed, and the authors demonstrated CD155 and its co-inhibitory receptor TIGIT could promote PDAC immune evasion. Combined treatment of orthotopic tumors with anti-CD40, anti-PD1, and anti-TIGIT provided durable tumor remissions, while no single or dual treatment was effective.

Expert Commentary: Blocking the CD155/TIGIT immune inhibitory axis in combination with other checkpoints overcomes PDAC immune evasion and reduces tumor burden in preclinical models.

Freed-Pastor WA, Lambert LJ, Ely A, Pattada NB, Bhutkar A, Eng G, et al. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer, Cancer Cell 2021:S1535-6108(21)00384-6. doi: 10.1016/j.ccell.2021.07.007.


Multiple myeloma, the second most common hematological cancer, develops in the bone marrow due to uncontrolled proliferation of malignant plasma cells. The Notch signaling pathway is dysregulated in multiple myeloma and this favors pathological communication between multiple myeloma and bone marrow cells. Gamma-secretase inhibitors (GSI) are used extensively to inhibit Notch in multiple myeloma, however, GSIs can cause undesirable, dose-limiting severe toxicities, restricting clinical application. Sabol and colleagues generated a bone-targeted Notch inhibitor (BT-GSI) which was targeted to the bone via a bisphosphonate group and contained a linker group that could be cleaved in the acidic environment in the bone to release the GSI. The authors demonstrated that systemic administration of BT-GSI selectively inhibits Notch signaling in bone/bone marrow but not in other tissues, overcoming the toxicity issues associated with this class of drugs. In mouse models of established multiple myeloma, BT-GSI inhibited multiple myeloma growth and bone destruction more effectively than the GSI alone

Expert Commentary: This study reports a bone-targeted BT-GSI that reduced multiple myeloma growth, diminished cancer-induced bone destruction, and did not induce gut or hematological toxicities typically found with systemic administration of GSIs.

Sabol HM, Ferrari AJ, Adhikari M, Amorim T, McAndrews K, Anderson J, et al. Targeting Notch inhibitors to the myeloma bone marrow niche decreases tumor growth and bone destruction without gut toxicity. Cancer Res 2021;81:5102–14.


The efficacy of EGFR targeted therapy is limited by the development of acquired resistance in non-small cell lung cancer. Resistance to EGFR inhibitors, such as osimertinib, frequently arises via non-EGFR–dependent mechanisms, so there is a need to identify therapies that can be combined with EGFR inhibitors to clear resistant tumor cells. Utilizing a high-throughput screening approach, with selection for compounds that enhanced osimertinib-induced apoptosis, Tanaka and colleagues demonstrated that targeting Aurora B kinase (AURKB) could enhance osimertinib-induced apoptosis and overcome resistance. AURK inhibitors were found to increase BIM and PUMA levels, resulting in increased osimertinib sensitivity and decreased drug-tolerant persisters. ATR-CHK1-AURKB pathway inhibition could also overcome epithelial-mesenchymal transition–associated resistance through mitotic cell death.

Expert Commentary: This study suggests that selecting osimertinib combination therapies that enhance apoptosis may improve duration of response and overcome resistance in the clinic.

Tanaka K, Yu HA, Yang S, Han S, Selcuklu SD, Kim K, et al. Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell 2021; S1535–6108(21)00383-4. doi: 10.1016/j.ccell.2021.07.006.

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.