In This Issue

See article, p. 1238.

The identification of actionable genetic alterations in tumors can guide personalized use of targeted therapies. Serra and colleagues report the case of a patient with recurrent breast and lung tumors that harbored a germline TP53 mutation and was diagnosed with Li-Fraumeni Syndrome. Whole-exome sequencing of the patient's tumors and metastases identified alterations in either EGFR or HER2 in each sample, suggesting that convergent evolution toward human epidermal growth factor receptor (HER) activation conferred a selective advantage. The patient's most recent tumor had a HER2^V659E mutation, an allele that had not previously been found in humans but is orthologous to the mutation found in rats that led to the discovery of HER2 as an oncogene. Overexpression of HER2^V659E in human mammary epithelial cells induced HER2 hyperphosphorylation and activation of downstream signaling, and cells expressing HER2^V659E were sensitive to clinically relevant concentrations of lapatinib, a small-molecule inhibitor of HER2 and EGFR. Based on these findings, lapatinib therapy was initiated in combination with paclitaxel, and led to symptom improvement and a radiologic response within 2 months. After paclitaxel was discontinued due to toxicity and amplified HER2 was detected in circulating tumor cells, trastuzumab was added, and disease stabilization continued for 6 more months. These results suggest that anti-HER2 therapies may also have clinical activity in tumors with HER2 mutations and raise the possibility that activation of HER family receptor tyrosine kinases contributes to the pathogenesis of Li-Fraumeni Syndrome.

See article, p. 1245.

The standard of care for men with high-risk prostate cancer is the combination of androgen deprivation therapy (ADT) and radiotherapy, which increases prostate cancer cell death and improves overall survival compared with radiotherapy alone. However, the molecular mechanisms underlying this therapeutic synergy and how androgen receptor (AR) activity promotes resistance to radiotherapy remain poorly understood. Polkinghorn and colleagues found that treatment with the second-generation antiandrogen ARN-509 decreased the expression of DNA repair genes in castration-resistant prostate cancer xenografts, suggesting that AR positively regulates DNA damage repair. In support of this idea, canonical AR transcriptional output was associated with enrichment of a DNA repair gene signature in primary, castration-sensitive human prostate cancer samples; 32 of these 144 genes were stimulated by androgen and directly regulated by AR binding. Androgen deprivation or treatment with ARN-509 decreased DNA repair in vitro, resulting in accumulation of DNA damage and reduced prostate cancer cell viability in response to ionizing radiation, whereas stimulation with androgens enhanced repair of radiation-induced DNA damage and conferred resistance to radiotherapy. This antiandrogen-stimulated increase in radiosensitivity was mediated by a reduction in DNA double-strand break repair via classical nonhomologous end-joining but not homologous recombination. These results establish AR as an important transcriptional regulator of DNA repair gene expression and suggest that inhibition of AR-driven DNA repair underlies the synergistic effects of ADT and ionizing radiation in men with prostate cancer.

See article, p. 1254.

Increased activity of DNA damage repair pathways such as nonhomologous end-joining has been implicated in tumor progression and resistance to radiation therapy, which induces DNA double-strand breaks. Clinical studies have shown that the combination of androgen deprivation therapy (ADT) and radiation therapy improves survival in men with prostate cancer, suggesting that androgen receptor (AR) activity may affect the response to radiation-induced DNA damage and radiosensitivity. Goodwin and colleagues found that ADT or pharmacologic AR inhibition decreased the growth and survival of castration-resistant prostate cancer (CRPC) cells and xenografts in response to radiation, and that this effect was rescued by androgen supplementation, indicating that AR activity promotes radioresistance. Consistent with this idea, AR signaling was activated in CRPC cells in response to DNA damage and promoted resolution of radiation-induced DNA double-strand breaks, independent of the role of AR in cell-cycle progression and apoptosis. AR-mediated DNA repair was dependent on direct induction of genes involved in DNA damage repair, in particular the gene encoding DNAPKcs (DNA-dependent protein kinase catalytic subunit). AR stimulated both the expression and activation of DNAPKcs in CRPC cells; DNAPKcs inhibition impaired DNA repair following radiation and reduced AR transcriptional activity, whereas androgen supplementation partially rescued double-strand break repair and enhanced radioresistance. These findings identify a positive feedback loop linking AR-mediated regulation of DNAPKcs to DNA damage repair and tumor progression and suggest that inhibition of this signaling axis may overcome radioresistance in CRPC.

See article, p. 1272.

Autophagy, a catabolic process in which unnecessary or defective cellular components are engulfed and lysosomally degraded, sustains cell survival by recycling metabolites for biosynthesis and eliminating damaged proteins and organelles. Whether autophagy limits or promotes tumorigenesis is unclear, although increasing evidence suggests the role of autophagy in cancer is context-dependent. Strohecker and colleagues evaluated the role of autophagy in tumor establishment and progression using a mouse model in which intranasal administration of adenoviral Cre recombinase simultaneously enabled expression of the Braf^V600E allele and deleted the essential autophagy gene Atg7 in the lung. Interestingly, inhibition of autophagy via Atg7 deletion initially induced oxidative stress and accelerated the formation of Braf^V600E-driven lung tumors, but progressive mitochondrial dysfunction eventually limited tumor proliferation and prolonged survival. Atg7 deficiency altered progression of Braf^V600E-driven tumors from adenomas and adenocarcinomas to benign oncocytomas that accumulated morphologically and functionally defective mitochondria, suggesting that defects in mitochondrial metabolism may suppress tumor growth. Analysis of tumor-derived cell lines revealed that Atg7-deficient cells were significantly more sensitive to starvation than Atg7–wild-type cells. Moreover, loss of Atg7 conferred dependence on exogenously supplied glutamine for survival. Taken together, these data suggest that Braf^V600E-driven tumors may become addicted to autophagy as a means to sustain proper mitochondrial function and meet their increased biosynthetic demands and, as a result, may be sensitive to compounds that block this process.

See article, p. 1286.

Synovial sarcoma, an aggressive cancer lacking effective therapies, is distinguished by a chromosomal translocation that fuses SYT (also known as SS18) on chromosome 18 with one of three SSX genes (SSX1, SSX2, or SSX4) on the X chromosome. The SYT–SSX fusion product has been shown to disrupt the activity of chromatin remodeling complexes and deregulate gene expression, but exactly how SYT–SSX drives tumorigenesis remains unclear. Using murine models of synovial sarcoma, Barham and colleagues show that activation of the WNT pathway is essential for the initiation and progression of synovial sarcoma. Deletion of β-catenin abrogated tumor formation in a conditional transgenic mouse model expressing human SYT–SSX2, and expression of the WNT receptor antagonist DKK1 or depletion of the WNT receptor LRP6 suppressed synovial sarcoma xenograft growth. Moreover, pharmacologic inhibition of the WNT pathway with activators of casein kinase 1α (CK1α), which stabilizes axin and promotes β-catenin turnover, significantly reduced human synovial sarcoma cell line growth in vivo and induced regression of established tumors. Activation of β-catenin activity by SYT–SSX was dependent on the same N-terminal segment necessary for interactions with chromatin remodelers that regulate gene expression, and expression of SYT–SSX led to transcriptional activation of many WNT pathway components in an autocrine manner. The finding that synovial sarcomas are dependent on SYT–SSX-induced WNT/β-catenin signaling suggests that targeting this pathway may improve clinical outcomes.

See article, p. 1302.

The oncogenic receptor tyrosine kinase EPH receptor A2 (EPHA2) is frequently overexpressed in ovarian cancer and has been associated with increased tumor growth and decreased overall survival, implicating EPHA2 as a potential therapeutic target. Although treatment with EPHA2-targeted siRNA decreases tumor growth in mouse models, the clinical efficacy of this approach has been limited, suggesting that additional targeting of the EPH pathway may boost the antitumor activity of EPHA2 siRNA. Nishimura and colleagues characterized a tumor-suppressive microRNA (miRNA, miR), miR-520d-3p, as a favorable prognostic factor in patients with ovarian cancer that directly targeted EPHA2. Restoration of miR-520d-3p expression in ovarian cancer cells downregulated EPHA2 expression, resulting in reduced proliferation, migration, and invasion in vitro and impaired tumor formation and angiogenesis in an orthotopic model of ovarian cancer. Moreover, combined treatment with EPHA2 siRNA and miR-520d-3p further enhanced the suppression of ovarian cancer cell proliferation and migration and synergistically inhibited tumor growth and angiogenesis in vivo compared with single-agent therapy. This increased antitumor efficacy was mediated in part by the ability of miR-520d-3p to also directly repress the expression of the EPH receptor EPHB2; low EPHA2/EPHB2 expression and high miR-520d-3p levels were associated with prolonged survival, suggesting that this prognostic signature may facilitate stratification of patients with ovarian cancer. These results establish combined siRNA and miRNA treatment as a potential strategy to improve therapeutic efficacy in ovarian cancer and potentially other tumors.

Note: In This Issue is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.