In This Issue

See article, p. 694

PD-1 blockade is approved to treat patients with metastatic non–small cell lung cancer. However, not all patients respond adequately to anti–PD-1 therapy, and it cannot overcome the effects of immunosuppressive myeloid-derived suppressor cells (MDSC) or regulatory T cells. Thus, combination immunotherapies may enhance the efficacy of PD-1 blockade. Activation of the complement system releases the active proteolytic fragment C5a, which promotes an immunosuppressive microenvironment to support lung cancer progression, prompting Ajona and colleagues to test PD-1 inhibition in combination with inhibition of C5a or its receptor C5aR1. In a mutant Kras-driven mouse model of lung adenocarcinoma, C5aR1 depletion reduced tumor size and extended survival. Similarly, C5a inhibition with an l-aptamer (AON-D21) that blocks the interaction with its receptors reduced tumor growth. Combined treatment with AON-D21 and anti–PD-1 suppressed the growth of syngeneic lung tumors more effectively than either therapy alone, resulting in complete tumor rejection in many cases. AON-D21 plus anti–PD-1 also reduced metastases and increased survival in a metastatic tumor model. Combined targeting of C5a and PD-1 increased the frequency of CD8⁺ T cells, which were required for the antitumor response, and reduced the frequency of MDSCs. Anti–PD-1 therapy plus MDSC depletion had similar effects to anti–PD-1 plus AON-D21, suggesting that C5a inhibition may relieve MDSC-mediated immunosuppression. Moreover, AON-D21 in combination with anti–PD-1 was effective against established tumors and promoted CD8⁺ T-cell activation. These findings support further investigation of combined immunotherapy targeting PD-1 and C5a in patients with lung cancer.

See article, p. 704

Activating mutations or amplifications in PIK3CA, which encodes the PI3K catalytic subunit p110α, can promote tumorigenesis and are prevalent in solid tumors. Taselisib, a potent PI3K inhibitor with greater activity against mutant PI3Kα isoforms than wild-type PI3Kα, blocks the ATP-binding pocket of the catalytic PI3K subunit to suppress PI3K signaling. Juric and colleagues evaluated the safety, tolerability, and activity of taselisib in a phase I dose-escalation study in patients with locally advanced or metastatic solid tumors. Treatment of mice with PIK3CA-mutant breast cancer xenografts with a range of doses of taselisib resulted in dose-dependent inhibition of tumor growth, and these findings were used to establish the human dose levels for the phase I trial. In total, 34 heavily pretreated patients were enrolled and treated with taselisib. Taselisib was well tolerated; 41% of patients developed adverse events of grade 3 or higher, but these events occurred only at doses higher than the selected dose for future studies. Taselisib achieved PI3K pathway inhibition, consistent with on-target effects. Of the 14 patients with known PIK3CA-mutant tumors, 5 (36%) achieved confirmed partial responses including 4 patients with breast cancer and 1 patient with non–small cell lung cancer, whereas no patient without PIK3CA-activating mutations responded. These findings suggest that single-agent taselisib is safe and has antitumor activity in patients with PIK3CA-mutant tumors, and further studies of taselisib are ongoing both as a single agent and in combination therapies.

See article, p. 716

The chemotherapeutic cytarabine (AraC) is often used to treat patients with acute myeloid leukemia (AML), but most patients eventually relapse. It has been suggested that a population of quiescent leukemic stem cells (LSC) are responsible for AraC resistance, but the molecular mechanisms underlying AML resistance have not been fully elucidated in vivo. Farge and colleagues used 25 naïve AML patient-derived xenografts (PDX) to evaluate the response to AraC. AraC treatment reduced AML disease burden in vivo, but unexpectedly reduced the number of LSCs as well as mature AML cells, suggesting that AraC resistance is not mediated by a refractory LSC population. Further, AraC treatment did not enrich for quiescent cells. Instead, AraC induced expression of genes involved in inflammation and stress responses in cells refractory to AraC, including genes involved in the response to reactive oxygen species (ROS). ROS levels were elevated in AraC-resistant cells, and mitochondria exhibited increased activity and mass, consistent with enhanced oxidative phosphorylation (OXPHOS). Indeed, AraC-resistant AML cells displayed high expression of OXPHOS genes compared with chemosensitive cells, and this high OXPHOS phenotype depended on mitochondrial oxidation of fatty acids. In vivo, cells with the high OXPHOS gene signature were detected before AraC treatment and enriched after AraC treatment. Resistant cells had increased mitochondrial respiration in vitro and in vivo, and inhibiting OXPHOS rendered resistant cells more sensitive to AraC. The finding that high OXPHOS activity is associated with chemoresistance in AML suggests that possibility for therapeutic targeting of mitochondrial metabolism to enhance chemosensitivity.

See article, p. 736

Castration-resistant prostate cancers (CRPC) often exhibit initial responses to therapies that target androgen receptor signaling or synthesis, such as abiraterone, but eventually aggressive resistant disease develops. These resistant tumors often exhibit features of small-cell carcinoma and neuroendocrine (NE) differentiation mixed with adenocarcinoma. This CRPC-NE histopathology is rare in localized prostate cancer, but often occurs in patients who fail to respond to androgen-deprivation therapy. Zou and colleagues evaluated the response to abiraterone in a mouse model of CRPC (NPp53) driven by loss of function of Pten and Trp53, which are frequently co-mutated in patients with CRPC, in the adult prostate epithelium. Abiraterone treatment failed to suppress CRPC tumor growth and even accelerated tumor growth in a subset of mice. In NPp53 tumors that displayed accelerated growth in response to abiraterone, genes expressed in human CRPC-NE were upregulated, including Sox11, a transcription factor previously implicated in neural differentiation. SOX11 depletion downregulated neuroendocrine markers, suggesting that abiraterone treatment–associated neuroendocrine differentiation may be mediated in part by SOX11. Neuroendocrine cells were rare in naïve NPp53 tumors, but became more abundant following castration or abiraterone treatment. In vivo lineage tracing showed that the neuroendocrine population arose via transdifferentiation of luminal adenocarcinoma cells. These findings reveal a mechanism by which abiraterone treatment can induce the progression from adenocarcinoma to CRPC-NE to promote drug resistance in CRPC.

See article, p. 750

Tyrosine kinase inhibitors (TKI) achieve clinical responses in multiple malignancies, but their effects on the tumor immune microenvironment are not well understood. Cabozantinib is a TKI with activity against multiple tyrosine kinases including RET and c-MET, and has been FDA approved for the treatment of RET-driven medullary thyroid cancer and clear cell renal cell carcinoma. It also showed promising activity in a phase II trial of patients with castration-resistant prostate cancer, but did not extend survival in a phase III trial, suggesting that a better understanding of its mechanism of action is required to identify patients who may respond to cabozantinib. Patnaik and colleagues found that, in a mouse model of Pten/Trp53-deficient prostate cancer, cabozantinib eradicated tumors via a c-MET independent mechanism. Cabozantinib induced tumor regression, whereas a specific c-MET inhibitor did not. Further, cabozantinib induced activation of neutrophil-mediated antitumor innate immunity, suggesting a mechanism for TKI-mediated tumor clearance. Cabozantinib had only modest effects in vitro, further supporting a dominant tumor-cell nonautonomous mechanism for its antitumor activity. Cabozantinib induced tumor cells to release the chemokines CXCL12 and HMGB1 into the tumor microenvironment, resulting in neutrophil infiltration. Neutrophils were required for cabozantinib-mediated tumor clearance, as neutrophil depletion or trafficking to the tumor abrogated the antitumor effects of cabozantinib. Collectively, these findings reveal that cabozantinib promotes prostate tumor clearance via a c-MET–independent neutrophil-mediated innate immune response, and suggest that combining cabozantinib with approaches that activate adaptive immune response warrant further investigation in patients with advanced cancer.

See article, p. 766

The DNA damage response (DDR) pathway is an integrated signaling pathway that coordinates the numerous responses required for a cell to maintain DNA integrity, including DNA repair and senescence, via proteins such as p53 (encoded by TP53), which is a central mediator of cellular damage responses. Having shown that ionizing radiation (IR) promotes the binding of RPL26 to TP53 mRNA and regulates TP53 translation, Chen and colleagues characterized the transcriptome bound by RPL26 and found that IR promoted alternative splicing of TP53 and that the TP53β variant was increased in the RPL26 immunocomplex. Pharmacologic inhibition and siRNA-mediated knockdown experiments revealed that IR promotes increased TP53β expression via inhibition of the ATM-related kinase SMG1. RPL26 bound to TP53 pre-mRNA and recruited the splicing factor SRSF7 to induce the alternative splicing of TP53β, which promoted markers of a senescent phenotype. IR-induced upregulation of TP53β resulted in increased senescence markers, but not apoptosis, of cell lines representing different tumor types, and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9–mediated knockdown of TP53β resulted in a loss of IR-induced cellular senescence markers. Similarly, ablation of SMG1 or SRSF7 resulted in, respectively, increased expression of cellular senescence markers or suppression of IR-induced cellular senescence markers. Further, IR was found to induce the alternative splicing of other genes, such as SMAD3, via SMG1/RPL26/SRSF7. These results characterize a previously unidentified arm of the DDR pathway that regulates DNA damage–induced alternative splicing in cancer, and demonstrate an apparent role in cellular senescence.

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