Search

KRAS mutations are among the most prevalent tumor drivers, but targeting them pharmacologically has been challenging. Recent landmark studies have demonstrated promising clinical results of KRAS^G12C inhibition by using small molecules. Bar-Sagi, and Knelson and Sequist provide their distinct perspectives on this recent tour de force in targeting KRAS^G12C alterations.

Burr et al. analyze multiple primary EGFR-mutant lung tumors from ten patients and define developmental mosaicism as a mechanism underlying multiple tumor presentation in this setting.

A method, RARE-seq, for sensitive detection of cell-free RNAs in blood is demonstrated to have diverse clinical applications including diagnosing and characterizing human cancers, and tracking response to RNA therapeutics.

Activating mutations in EGFR are characteristic of patients with lung cancer who have high sensitivity to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. The randomized IPASS study by Mok and colleagues confirmed that patients with EGFR mutations have a higher response rate, longer progression-free survival and improved quality of life when treated with first-line gefinitib instead of chemotherapy.

Induction of APOBEC3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that its suppression may represent a potential therapeutic strategy in the prevention of acquired resistance to lung cancer targeted therapy.

A microfluidic platform that is capable of efficiently and selectively separating viable circulating tumour cells (CTCs) from peripheral blood samples has been developed. Low levels of CTCs in the peripheral blood of patients with various cancers were identified, and it was shown that this device could be used to monitor an individual patient's response to anti-cancer therapy.

Circulating tumor cells (CTCs) are clinically useful for detecting and monitoring cancer, but they are rare in blood. Here, the authors use a highthroughput microfluidic device to massively enrich CTCs from leukapheresis products to uncover single cell molecular features in prostate and other cancers.

Circulating tumour DNA in blood is analysed to identify genomic features that distinguish early-stage lung cancer patients from risk-matched controls, and these are integrated into a machine-learning method for blood-based lung cancer screening.

Circulating tumour cells contribute to metastatic spread. Here the authors find that beta-chain of haemoglobin is overexpressed in those cells and protects them from oxidative stress, prolonging their survival in circulation and thereby increasing the likelihood of metastasis formation.

Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process.

Extracellular vesicles can carry many different types of biological cargo and have been investigated as a biomarker for cancer diagnosis. Here the authors develop a microfluidic platform for rapid and sensitive isolation of tumor-specific extracellular vesicles.

Drug-tolerant but initially EGFR^T790M-negative tumor cells that undergo genetic evolution to acquire resistance to EGFR inhibitors are more resistant than pre-existing EGFR^T790M -positive clones to subsequent therapy.

EGFR-mutant non-small cell lung cancer is routinely treated with EGFR inhibitors, although resistance inevitably develops. Here, the authors sequence circulating tumour DNA and show that resistance to the third-generation inhibitor rociletinib is heterogeneous and recurrently involves somatic alterations of MET, EGFR, PIK3CA, ERRB2, and KRAS.

The current FDA-approved whole blood stabilization method for circulating tumor cell (CTC) isolation suffers from RNA degradation. Here the authors combine hypothermic preservation and antiplatelet strategies to stabilize whole blood up to 72 h without compromising CTC yield and RNA integrity.

Circulating tumour cells (CTCs) might be representative of the tumour burden and might also provide information on tumour cell biology. As such, these cells hold promise in the prediction and monitoring of response to anticancer therapy. In this Review, the authors highlight the challenges of monitoring treatment response in metastatic castrate-resistance prostate cancer and discuss the developments in CTC analyses that have increased the value of these cells as potential biomarkers in this disease.

This Review explores breakthroughs in our understanding and treatment of acquired resistance to tyrosine kinase inhibitors in key molecular subtypes of non-small-cell lung cancer, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. The potential of a number of clinical approaches to treat acquired resistance, from new drugs or drug combinations through to the use of more traditional therapies such as radiation or cytotoxic chemotherapy, are highlighted, and the implications for major changes in conducting clinical research in this setting are discussed.

A new method allows the collection of circulating tumour cells (CTCs) despite their rarity; transcriptome sequencing of CTCs could allow identification of pathways involved in metastasis.

Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area.