MET Amplification Drives Resistance to Combined EGFR/BRAF Blockade
See article, p. 963.
MET amplification drives resistance to dual therapy targeting EGFR and BRAF in BRAF-mutant tumors.
A patient resistant to BRAF/EGFR blockade had an early response to ongoing MET/BRAF inhibition.
Dual MET and BRAF blockade may be effective in patients who develop MET-driven resistance.
Targeted therapies to treat patients with metastatic BRAF-mutant colorectal cancer have been developed, including combinations targeting EGFR, BRAF, MEK, and/or PI3K. The rapid acquisition of drug resistance blunts the efficacy of targeted therapies, but the resistance mechanisms remain incompletely characterized. Pietrantonio, Oddo, and colleagues identified a mechanism of resistance to dual EGFR and BRAF blockade in a patient with BRAFV600E-mutant metastatic colorectal cancer who developed resistance to the anti-EGFR antibody panitumumab plus the BRAF inhibitor vemurafenib. The acquired resistance was associated with subclonal amplification of MET and increased MET expression, suggesting that inhibition of EGFR and BRAF selected for MET-amplified clones. In vitro, MET overexpression activated ERK signaling and rendered BRAF-mutant colorectal cancer cells resistant to vemurafenib and panitumumab, and sensitivity was restored by treatment with the MET inhibitor crizotinib. Cells with MET amplification were resistant to EGFR, BRAF, and MEK inhibitors alone or in combination, and crizotinib, which had no effect alone, reduced cell viability in combination with vemurafenib. Based on these findings, the patient was treated with combined crizotinib and vemurafenib to target MET and BRAF. A dramatic early response was achieved, and treatment is ongoing without significant toxicity. The identification of a mechanism of MET-driven resistance to BRAF/EGFR blockade in a patient with BRAF-mutant colorectal cancer indicates that MET inhibitors may warrant further investigation in biomarker-driven clinical trials in combination with BRAF inhibition or with dual EGFR and BRAF inhibition.
Activation of a TCR-Dependent Checkpoint Suppresses T-ALL
See article, p. 972.
TCR stimulation via antigen/MHC presentation or anti-CD3 mAb induces T-ALL cell death.
Anti-CD3 mAb reactivates a program similar to thymic negative selection during development.
Targeting CD3 impairs the growth of mouse- and patient-derived T-ALL xenografts.
T-cell acute lymphoblastic leukemia (T-ALL) arises from leukemic transformation and expansion of immature T-cell precursors. During normal thymic development, T cells mature via cell surface expression of the T-cell receptor (TCR) and positive selection of thymocytes that bind self-peptide/MHC complexes with low affinity. In contrast, thymocytes that recognize self-peptide/MHC with high affinity undergo negative selection via TCR-mediated apoptosis, prompting Trinquand, dos Santos, Tran Quang, and colleagues to hypothesize that reactivation of this developmental checkpoint in T-ALL cells may have antileukemic activity. Consistent with this idea, persistent stimulation of TCR signaling by high-affinity antigen/MHC complexes triggered apoptosis of T-ALL cells in vitro and delayed T-cell leukemogenesis in mice. Furthermore, treatment of both mouse and primary human T-ALL cells with an agonistic mAb targeting a component of the TCR complex, CD3, activated TCR signaling and resulted in TCR-dependent apoptosis. The induction of apoptosis in primary human T-ALL cells was associated with enrichment of a transcriptional program similar to the signature of TCR-driven negative selection of thymic progenitors. Moreover, anti-CD3 mAb treatment impaired leukemia development and prolonged survival in mouse models of TCR-expressing T-ALL and mice transplanted with patient-derived CD3-positive T-ALL. This tumor-suppressive effect was dependent on activation of TCR signaling, as depletion of the TCR adaptor protein LAT suppressed anti-CD3–mediated tumor cell apoptosis. These findings support the notion that reactivation of the lineage-specific TCR negative selection checkpoint has antileukemic effects and suggest that anti-CD3 treatment may be therapeutically beneficial in T-ALL.
IL15 Promotes Cutaneous T-cell Lymphoma Tumorigenesis
See article, p. 986.
IL15 overexpression can induce cutaneous T-cell lymphoma (CTCL) via induction of HDAC1/6 and miR-21.
Hypermethylation of the IL15 promoter prevents ZEB1 binding, enhancing IL15 expression.
Specific HDAC inhibitors may enhance HDAC inhibitor safety and efficacy to reduce CTCL progression.
The oncogenic drivers of cutaneous T-cell lymphoma (CTCL) development are largely unknown, and no curative therapies are available. Pan-histone deacetylase (HDAC) inhibitors have been approved to treat CTCL, but are associated with low response rates and some toxicity. IL15 supports T-cell lymphoma cell growth, prompting Mishra and colleagues to investigate its role in CTCL tumorigenesis. IL15 was highly expressed in CD4+ T cells from patients with CTCL, and overexpression of IL15 in mice resulted in the development of spontaneous CTCL that resembled the human disease. In CD4+ T cells from patients with CTCL, a CpG-rich region of the IL15 promoter that contained binding sites for the transcriptional repressor ZEB1 was hypermethylated, which blocked ZEB1 binding and upregulated IL15. Further, elevated IL15 expression upregulated the histone deacetylases HDAC1 and HDAC6 at least in part by reducing binding of HDAC1 to the HDAC1 and HDAC6 promoters, where it normally binds to repress transcription. HDAC1 enhanced transcription of the oncogenic miR-21, which was overexpressed in patients with CTCL. Treatment of CTCL cells with specific HDAC inhibitors targeting HDAC1/2 or HDAC6 revealed that cells were more sensitive to HDAC1/2 inhibition than HDAC6 inhibition. In vivo, HDAC6 inhibition delayed tumor progression, whereas HDAC1/2 inhibition halted tumor growth and, in some cases, induced tumor regression. Collectively, these findings elucidate a mechanism by which IL15 drives CTCL tumorigenesis and support clinical investigation of specific HDAC inhibitors in patients with CTCL to potentially improve the safety and efficacy of HDAC inhibition in CTCL.
EZH2 May Be a Therapeutic Target in NSCLC Driven by Its Overexpression
See article, p. 1006.
EZH2 overexpression induces NSCLC-like tumors that are distinct from KRAS- or EGFR-driven tumors.
EZH2 overexpression alters chromatin structure to disrupt normal developmental pathways.
A newly developed EZH2 inhibitor, JQEZ5, promotes tumor regression in EZH2-dependent NSCLC.
Increased expression of the histone methyltransferase EZH2 has been linked to poor outcomes in lung adenocarcinoma, suggesting it may be an oncogenic driver and potential therapeutic target in non–small cell lung cancer (NSCLC). Zhang, Qi, and colleagues showed that EZH2 is sufficient to transform lung epithelial cells in transgenic mouse models overexpressing EZH2, with approximately 40% of mice developing lung adenocarcinoma. These tumors exhibited reduced phosphorylation of AKT and ERK compared with mutant KRAS–driven tumors and exhibited transcriptome profiles that were distinct from EGFR-mutant and KRAS-mutant tumors. These murine tumors corresponded to a subset of human NSCLCs in The Cancer Genome Atlas that highly overexpressed EZH2 but had wild-type KRAS and EGFR. EZH2-induced global changes in chromatin structure; a subgroup of cis-regulatory regions exhibited loss of H3K27ac, a mark enriched at superenhancers, and concomitant H3K27me3 gain, reducing expression of a number of developmental transcriptional regulators, whereas superenhancer gain at other regions increased expression of negative regulators of MAPK–ERK signaling. EZH2 knockdown in human lung adenocarcinoma cell lines expressing high levels of EZH2 reduced growth in vitro and in tumor xenografts, indicating dependence on EZH2 expression. To exploit this dependence, an enzymatic EZH2 inhibitor, JQEZ5, was developed. Treatment of tumor-bearing EZH2-overexpressing mice with JQEZ5 resulted in tumor regression and reduced H3K27me3. In addition to demonstrating the efficacy of JQEZ5, these results indicate that EZH2 overexpression drives a subset of NSCLCs that may be therapeutically targeted EZH2-addicted tumors.
Autocrine Complement Inhibits IL10-Mediated Antitumor Immunity
See article, p. 1022.
T cell–derived C3a inhibits T cell–mediated IL10 production and effector T-cell differentiation.
Complement-driven inhibition of antitumor immunity is independent of the immune checkpoint PD-1.
Targeting complement signaling and enhancing IL10 production many improve antitumor immunity.
IL10 both suppresses and promotes inflammation by inhibiting the production of proinflammatory cytokines by macrophages and Th1 T cells and inducing the activation and expansion of CD8+ tumor-infiltrating lymphocytes (TIL) to promote antitumor immunity in animal models, respectively. However, due to the pleiotropic effects of IL10, systemic IL10 may potentially decrease antitumor immunity and may even promote tumorigenesis. To determine whether IL10 production could be induced in CD8+ TILs, Wang and colleagues interrogated the gene expression profiles of IL10+CD8+ T cells and IL10−CD8+ T cells for potential regulators of IL10 and showed that complement signaling was highly upregulated in IL10+CD8+ T cells. Transgenic mouse studies revealed that complement signaling inhibited IL10production in CD8+ TILs, and melanoma- and breast cancer–bearing complement 3 (C3)–depleted mice exhibited enhanced IL10-dependent CD8+ TIL–mediated antitumor immunity. In vivo experiments using chimeric mice showed that autocrine C3 inhibited IL10 production by CD8+ TILs, which exhibited high levels of C3a receptor (C3aR) or C5aR. Similarly, blockade of C3aR or C5aR restored IL10 production in CD8+ TILs and inhibited tumor growth in vivo, suggesting that C3aR and C5aR may be immune checkpoint receptors. Further, although complement inhibited antitumor immunity independent of the programmed cell death 1 (PD-1) pathway, PD-1 inhibition enhanced the antitumor effects of complement receptor blockade. These findings describe the role of the complement/IL10 axis in mediating antitumor immune responses and have implications for designing cancer immunotherapy strategies.
miR-3662 Regulates Hematopoietic Differentiation and Leukemogenesis
See article, p. 1036.
miR-3662 is a driver of phenotypes associated with the hematopoietic QTL in chromosome 6q23.3.
Expression of miR-3662 is upregulated by GATA1 and CEBPα and inhibits leukemogenesis.
miR-3662 represses IKBKB to inhibit NF-κB signaling and promote hematopoietic differentiation.
The chromosome 6q23.3 quantitative trait locus (QTL) harbors many SNPs identified by genome-wide association studies (GWAS) and three protein-coding genes, including HBS1-like translational GTPase (HBS1L), associated with hematopoietic differentiation. Maharry and colleagues investigated whether miR-3662, which was recently identified in intron 13 of HBS1L, is involved in hematopoietic development and leukemogenesis. It was shown that miR-3662 abundance is low in both normal undifferentiated hematopoietic progenitor (HP) cells and leukemic cells. miR-3662 was associated with the risk variants of the GWAS SNPs in the 6q23.3 locus, including rs66650371, which was shown to modulate miR-3662 expression via alteration of transcription factor (GATA1 and the p30 isoform of C/EBPα) binding sites. Overexpression of miR-3662 induces HP cell growth and differentiation, and reduced the growth and clonogenic potential of acute myeloid leukemia in vitro and inhibited tumor growth and leukemogenesis in vivo. Pathway analysis of targeted RNA-sequencing data revealed that miR-3662 expression associates with various cellular growth–related pathways such as proliferation, survival, and cell death. Further, miR-3662 inhibits NF-κB signaling through the downregulation of inhibitor of kappa light polypeptide gene enhancer in B cells, kinase beta (IKBKB), suggesting that IKBKB is critical for the establishment of the miR-3662–induced differentiated phenotype. Together, these findings provide additional insights on the 6q23.3 QTL and the role of miR-3662 in normal and malignant hematopoiesis.
Cross-Cancer Meta-Analysis Identifies Pleiotropic Risk Loci
See article, p. 1052.
A cross-cancer meta-analysis was performed on breast, ovarian, and prostate cancer GWAS data.
Seven pleiotropic risk loci were associated with at least two cancer types.
Three risk loci associated with all three cancers were enriched for apoptosis-related genes.
Breast, ovarian, and prostate cancers are hormone-related cancers that tend to cluster in families, but the identification of risk loci for these cancers has been mostly site-specific. To identify susceptibility loci with pleiotropic associations for hormone-related cancers, Kar and colleagues performed meta-analyses of 228,786 individuals from genome-wide association studies (GWAS) of breast, ovarian, and prostate cancers. The meta-analyses revealed that five loci previously associated with one of the three cancers were found to exhibit associations with a second cancer, and identified seven pleiotropic loci which were over 1 Mb from known risk alleles and had not been previously correlated with any of the three cancers. Three of the seven loci were associated with all three cancers, and the other four were associated with two of the three cancers. Expression quantitative trait locus (eQTL) analysis and annotation of enhancer maps revealed cell type–specific eQTL and enhancer-gene interactions for several genes, including GATA zinc finger domain containing 2A (GATAD2A) in all three cancers. Pathway-based analysis of genomic intervals associated with breast, ovarian, and prostate cancers identified genes related to apoptosis, suggesting that the induction of apoptosis may mediate susceptibility to all three cancers. Taken together, these results describe the largest cross-cancer GWAS meta-analysis to date and demonstrate the potential of large pan-cancer GWAS studies to identify pleiotropic risk variants and provide insight into shared biological processes that underlie susceptibility to different cancers.
Note: In This Issue is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details.
- ©2016 American Association for Cancer Research.