Therapeutic resistance is a major challenge in cancer treatment. In this issue of Cancer Cell, Kurppa et al. demonstrated that a senescence-like state enables lung cancer cells to survive dual inhibition of EGFR and MEK. This was mediated by the YAP/TEAD pathway, which drives epigenomic reprogramming and EMT to counteract apoptosis.

Drugs that target KRAS 12C covalently, AMG 510 and MRTX849, are now in the clinic. Recent papers describe development of these compounds, their selectivity and properties, early clinical data, and potential combination therapies. These papers herald a new era in Ras research, with improved drugs and strategies certain to follow.

In a recent issue of Science, Russo et al. observe that colorectal cancer cells, when exposed to the pressure of EGFR- and BRAF-targeted therapies, transiently alter their transcriptional profiles to foster mutagenesis, thereby enhancing the stochastic development of acquired resistance mutations.

Metastatic cancer is a major cause of death and remains largely incurable. A better understanding of metastasis is therefore desperately needed to improve prognosis for late-stage disease. Here we survey the landscape of studies exploring the genomics of metastatic cancer. We consider evidence for genomic drivers of metastasis and explore studies investigating modes of metastatic spread.

Carcinogen-induced cancers typically have high mutation burdens and an inflamed microenvironment and thus are poised to respond to immune checkpoint inhibitors (ICIs). However, cancers with loss-of-function mutations in the SWI/SNF complex have few additional mutations yet also have an inflamed immunophenotype and should respond to ICI therapy.

There is increasing appreciation of the microbial influence on cancer, with emerging evidence about the tumor microbiome and crosstalk with the gut microbiome. A great example of this is pancreatic cancer, in which intra-tumoral microbes such as bacteria and fungi have been shown to contribute to carcinogenesis and therapeutic responses, both positively and negatively.

The combination of ipilimumab and nivolumab was evaluated versus standard treatments in melanoma and lung cancer. Analysis of these trials highlights the differences in outcomes and potential predictive biomarkers across tumor types as well as the multiple remaining questions concerning the optimal use of immune checkpoint inhibitors.

Adenosine is a key metabolic and immune-checkpoint regulator implicated in the tumor escape from the host immune system. Major gaps in knowledge that impede the development of effective adenosine-based therapeutics include: (1) lack of consideration of redundant pathways controlling ATP and adenosine levels; (2) lack of distinction between receptor-dependent and -independent effects of adenosine, and (3) focus on extracellular adenosine without consideration of intracellular metabolism and compartmentalization. In light of current clinical trials, we provide an overview of adenosine metabolism and point out the need for a more careful evaluation of the entire purinome in emerging cancer therapies.

Despite the role of STAT3 as a known driver of oncogenesis, efforts to develop therapeutic STAT3 inhibitors have thus far been unsuccessful. In this issue of Cancer Cell, Bai et al. report a potent and selective STAT3 degrader capable of producing complete and long-lasting tumor regression in mouse xenograft models.

In this issue of Cancer Cell, Quereda and colleagues report that a newly developed specific inhibitor of CDK12/13, SR-4835, sensitizes triple-negative breast cancer cells to PARP inhibitors and DNA-damaging chemotherapeutics by reducing expression of the genes in the DNA damage response pathway.

In this issue of Cancer Cell, Pillarsetty and colleagues radiolabel the potential anticancer drug PU-H71 and use it with PET imaging to quantify the epichaperome protein complex in tumors and its inhibition by the drug. They thereby develop a companion diagnostic paradigm of probe-drug pairing to explore therapeutic potential.

Immunotherapy has been the most effective in tumors with high mutational burden. However, a recent study in Cell by Wolf et al. demonstrates that high intratumor heterogeneity (ITH) for cancer neoantigens paradoxically attenuates anti-tumor immune responses, suggesting a need to quantify ITH to improve patient selection for checkpoint blockade therapy.

Stress has long been suspected to negatively influence cancer mortality, yet the molecular mechanisms responsible for this effect have only recently been identified. A new study identifies a stress-induced response in dendritic cells—the activation of the glucocorticoid-inducible transcriptional regulator TSC22D3—as a potent, immunosuppressive effect of stress on cancer.

Checkpoint blockade (CPB) therapy can elicit durable clinical responses by reactivating an exhausted immune response. However, response rates remain limited, likely secondary to a lack of a tumor-reactive immune infiltrate. Chimeric antigen receptor (CAR) T cells may provide the necessary tumor-targeting immune infiltrate and a highly specific antitumor immune response. This can be further amplified by the addition of CPB agents, which serve to counteract the immune inhibitory environment undermining optimal CAR T cell efficacy. Herein, we review preclinical and clinical combination therapy with CAR T cells and CPB agents, with a focus on solid tumor malignancies.

In this issue of Cancer Cell, Guièza et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax.

In this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells.

Mechanisms of acquired resistance to ALK inhibition therapy in neuroblastoma have not yet been elucidated. In a recent issue of Nature, Debruyne et al. demonstrate that resistant MYCN-amplified ALK-mutated neuroblastoma cells overexpress BORIS, resulting in wide-ranging changes in chromatin interaction and transcriptional reprogramming.

Recent approvals of TRK inhibitors have demonstrated the success of a tumor agnostic approach to oncogene-targeted therapy across cancers. Collective data from acquired resistance studies suggest that resistance mechanisms, which include both kinase domain mutations and bypass signaling via RTK-RAS-RAF-MAPK pathways, frequently recur regardless of tumor type, oncogene, and drug.

Widespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free DNA (cfDNA) fragments exhibit mutations. The cellular processes occurring in cancer development mark the chromatin. These epigenetic marks are reflected by modifications in the cfDNA methylation, fragment size, and structure. In this review, we describe how going beyond DNA sequence information alone, by analyzing cfDNA epigenetic and immune signatures, boosts the potential of liquid biopsy for the early detection of cancer.

BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1T315I-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.

The genetic concept of synthetic lethality provides a framework for identifying genotype-selective anticancer agents. In this approach, changes in cellular physiology that arise as a consequence of oncogene activation or tumor suppressor gene loss, rather than oncoproteins themselves, are targeted to achieve tumor selectivity. Here we show that agonists of the TRAIL death receptor DR5 potently induce apoptosis in human cells overexpressing the MYC oncogene, both in vitro and as tumor xenografts in vivo. MYC sensitizes cells to DR5 in a p53-independent manner by upregulating DR5 cell surface levels and stimulating autocatalytic processing of procaspase-8. These results identify a novel mechanism by which MYC sensitizes cells to apoptosis and validate DR5 agonists as potential MYC-selective cancer therapeutics.

The prognostication of head and neck squamous cell carcinoma (HNSCC) is largely based upon the tumor size and location and the presence of lymph node metastases. Here we show that gene expression patterns from 60 HNSCC samples assayed on cDNA microarrays allowed categorization of these tumors into four distinct subtypes. These subtypes showed statistically significant differences in recurrence-free survival and included a subtype with a possible EGFR-pathway signature, a mesenchymal-enriched subtype, a normal epithelium-like subtype, and a subtype with high levels of antioxidant enzymes. Supervised analyses to predict lymph node metastasis status were approximately 80% accurate when tumor subsite and pathological node status were considered simultaneously. This work represents an important step toward the identification of clinically significant biomarkers for HNSCC.

We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.

Nucleophosmin (NPM, B23) is an abundant nucleolar phosphoprotein involved in ribosome biogenesis, and interacts with tumor suppressor proteins p53 and Rb. Here we show that NPM is a UV damage response protein that undergoes nucleoplasmic redistribution and regulates p53 and HDM2 levels and their interaction. By utilizing RNAi approaches and analyses of endogenous and ectopically expressed proteins, we demonstrate that NPM binds HDM2 and acts as a negative regulator of p53-HDM2 interaction. Viral stress, enforced by expression of Kaposi's sarcoma virus K cyclin, causes NPM redistribution, K cyclin-NPM association, and p53 stabilization by dissociation of HDM2-p53 complexes. The results demonstrate novel associations of HDM2 and K cyclin with NPM and implicate NPM as a crucial controller of p53 through inhibition of HDM2.

Inappropriate transcriptional repression involving histone deacetylases (HDACs) is a prominent cause for the development of leukemia. We now identify faulty expression of a specific mediator of transcriptional repression in a solid tumor. Loss of the adenomatosis polyposis coli (APC) tumor suppressor induces HDAC2 expression depending on the Wnt pathway and c-Myc. Increased HDAC2 expression is found in the majority of human colon cancer explants, as well as in intestinal mucosa and polyps of APC-deficient mice. HDAC2 is required for, and sufficient on its own to prevent, apoptosis of colonic cancer cells. Interference with HDAC2 by valproic acid largely diminishes adenoma formation in APC(min) mice. These findings point toward HDAC2 as a particularly relevant potential target in cancer therapy.

Tumors develop through successive stages characterized by changes in gene expression and protein function. Gene expression profiling of pancreatic islet tumors in a mouse model of cancer revealed upregulation of cathepsin cysteine proteases. Cathepsin activity was assessed using chemical probes allowing biochemical and in vivo imaging, revealing increased activity associated with the angiogenic vasculature and invasive fronts of carcinomas, and differential expression in immune, endothelial, and cancer cells. A broad-spectrum cysteine cathepsin inhibitor was used to pharmacologically knock out cathepsin function at different stages of tumorigenesis, impairing angiogenic switching in progenitor lesions, as well as tumor growth, vascularity, and invasiveness. Cysteine cathepsins are also upregulated during HPV16-induced cervical carcinogenesis, further encouraging consideration of this protease family as a therapeutic target in human cancers.

Through a poorly understood mechanism, tumors respond to radiation by secreting cytokines capable of inhibiting apoptosis in endothelial cells, thereby diminishing treatment response by minimizing vascular damage. We reveal here that this pathway is governed by a major angiogenesis regulator, HIF-1. Following radiotherapy, tumor reoxygenation leads to: (1) nuclear accumulation of HIF-1 in response to reactive oxygen, and (2) enhanced translation of HIF-1-regulated transcripts secondary to stress granule depolymerization. The resulting increase in HIF-1-regulated cytokines enhances endothelial cell radioresistance. Inhibiting postradiation HIF-1 activation significantly increases tumor radiosensitivity as a result of enhanced vascular destruction. These data describe novel pathways contributing significantly to our understanding of HIF-1 regulation which may be major determinants of tumor radiosensitivity, potentially having high clinical relevance.

The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.

Studies have shown that epidermal growth factor receptor (EGFR) signaling is important to normal development and neoplastic transformation, and that EGFR inhibition reduces cancer cell proliferation. The promising response rates of the EGFR inhibitor gefitinib in patients with chemotherapy-refractory non-small cell lung cancer (NSCLC) led to its approval for clinical use. However, there was little understanding of why gefitinib was effective in only some NSCLC patients. Two recent studies have identified somatic mutations in EGFR that confer its sensitivity to gefitinib in vitro and correlate strongly with patients' clinical response to the inhibitor.

Cysteine cathepsins are involved in degradation of extracellular matrix, facilitating growth, invasion, and metastasis of tumor cells, in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. In this issue of Cancer Cell, demonstrate association of increased cathepsins activity with angiogenic vasculature and invasive fronts of carcinomas during tumorigenesis in transgenic mouse models using activity-based chemical probes and in vivo imaging. Moreover, this study shows that a broad-spectrum cysteine cathepsin inhibitor effectively blocks several stages of tumorigenesis in the RIP1-Tag2 transgenic mouse model, offering new therapeutic opportunities in cancer treatment.