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Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a ‘one-two punch’ sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy.This Review discusses how senescence can be induced in cancer cells and how distinctive features of senescent cancer cells might be exploited for their selective eradication as a potential cancer therapy.

Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.This Review discusses the current and emerging therapeutic landscape for treatment of advanced hepatocellular carcinoma, including molecular-targeted monotherapies, immuno-oncology monotherapies, combination therapies and novel therapeutic approaches.

A major limitation of targeted anticancer therapies is intrinsic or acquired resistance. This review emphasizes similarities in the mechanisms of resistance to endocrine therapies in breast cancer and those seen with the new generation of targeted cancer therapeutics. Resistance to single-agent cancer therapeutics is frequently the result of reactivation of the signaling pathway, indicating that a major limitation of targeted agents lies in their inability to fully block the cancer-relevant signaling pathway. The development of mechanism-based combinations of targeted therapies together with non-invasive molecular disease monitoring is a logical way forward to delay and ultimately overcome drug resistance development. •Resistance to cancer (targeted) therapies remains a major problem in the clinic.•We highlight similarities between resistance mechanisms to different targeted therapies.•Resistance to targeted monotherapy is frequently driven by pathway reactivation.•Rational combinations of targeted therapies need to be developed.•Non-invasive molecular disease monitoring shows promise to guide these combinations.

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.Progress in precision medicine for colorectal cancer continues to lag behind the rapid improvements seen in patients with certain other solid tumour types. Nonetheless, owing largely to the availability of better translational models, novel and effective targeted therapy strategies based on tumour biology are beginning to be developed for subsets of patients. In this Review, the authors summarize these developments and discuss future directions in this rapidly evolving area of research.

[...]there is an urgent need to develop new drugs for PLC treatment, but a lack of suitable preclinical models that mimic key tumor characteristics is a major impediment. [...]the authors conclude that the G6PD inhibitor is a potential therapeutic agent for the L-DM subtype. Interestingly, an increasing number of PDO-based clinical trials in recent years suggest a trend towards an increasing reliance on PDOs for clinical decision-making in personalized medicine. [...]the new therapeutic targets and potential drug combinations for liver cancer predicted by the multi-omics data of LICOB deserve to be advanced to preclinical and clinical studies for validation as it may bring new therapeutic opportunities for liver cancer. [...]the lack of immune components hinders predictive modeling of immunotherapeutic responses.

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs) 1 – 3 . Inhibition of the RAS oncoproteins has proven difficult 4 , and attempts to target downstream effectors 5 – 7 have been hampered by the activation of compensatory resistance mechanisms 8 . It is also well established that KRAS -mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers 9 , 10 . Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS–RAF–MEK–ERK pathway 11 , 12 , was shown to be ineffective in KRAS -mutant or BRAF -mutant cancer cell lines 13 . Our data also indicate that SHP2 inhibition in KRAS -mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor–limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS -mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS -mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically. Combined inhibition of SHP2 and MEK is an effective therapeutic approach in non-small-cell lung cancer.

CRISPR knockout screens outperform shRNA and CRISPR-interference screens in a side-by-side comparison. High-throughput genetic screens have become essential tools for studying a wide variety of biological processes. Here we experimentally compare systems based on clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) or its transcriptionally repressive variant, CRISPR-interference (CRISPRi), with a traditional short hairpin RNA (shRNA)-based system for performing lethality screens. We find that the CRISPR technology performed best, with low noise, minimal off-target effects and consistent activity across reagents.

The success of cancer therapies is hampered by a paucity of suitable drug targets and the rapid development of therapy resistance. The concept of synthetic lethality provides a potential solution to these constraints via the identification of novel therapeutic vulnerabilities, as exemplified in two recent studies.

Killing cancer cells can have undesired side effects. Upon drug treatment, drug-sensitive cancer cells secrete an array of growth factors that stimulate the proliferation and dissemination of drug-resistant cells in the population.

Over the past two decades, elucidation of the genetic defects that underlie cancer has resulted in a plethora of novel targeted cancer drugs. Although these agents can initially be highly effective, resistance to single-agent therapies remains a major challenge. Combining drugs can help avoid resistance, but the number of possible drug combinations vastly exceeds what can be tested clinically, both financially and in terms of patient availability. Rational drug combinations based on a deep understanding of the underlying molecular mechanisms associated with therapy resistance are potentially powerful in the treatment of cancer. Here, we discuss the mechanisms of resistance to targeted therapies and how effective drug combinations can be identified to combat resistance. The challenges in clinically developing these combinations and future perspectives are considered.Single-agent therapies targeting specific dysregulated pathways in cancer can be highly effective, but drug resistance frequently develops. Here, Bernards and colleagues discuss the mechanisms underlying resistance to targeted therapies, and assess how these can be suppressed by using tailored combination therapies.