Series on Cancer Therapy

Cancer therapies have evolved considerably in recent decades, substantially improving the quality of life and survival of patients with cancer. In this issue, we launch our Series on Cancer Therapy, exploring current paradigms and recent advances and challenges in this field, through specially commissioned articles.

Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.

Zhou and colleagues discuss the opportunities and challenges in targeting public neoantigens for cancer immunotherapy.

Passaro and colleagues discuss recent advances in treating EGFR-mutant lung cancer, including methods for detecting disease and tracking therapy response, developments in understanding of resistance mechanisms and ongoing clinical trials to circumvent therapeutic resistance to EGFR targeting.

Kang and colleagues review recent advances and challenges in developing therapies for metastatic cancer and the clinical implications of ongoing and completed studies for metastatic disease.

Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.

The deployment of molecular biomarkers that are indicative of sensitivity to tumor-targeted or immune-targeted cancer therapies improves the outcome of individual patients and increases the chances of successful drug approval. However, for many lethal malignancies, the majority of clinical trials are conducted with patients who do not have biomarkers and hence they miss the target.

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.

Beyond the suffering caused by the disease, most patients diagnosed with cancer in the USA face substantial financial hardships associated with their treatments. What underlies the financial toxicity of cancer?

Precision oncology trials based on cancer biomarkers have the potential to improve outcomes by guiding the optimal choice of therapies for patients. For this to be truly achieved, computational methods such as virtual molecular tumor boards, dynamic precision medicine and digital twins are needed to support cohort selection and trial enrollment at scale.

Although RET alterations are relatively frequent across tumor types, specific targeting of RET in the clinic has been challenging. Ambrogio, Aggarwal and colleagues provide their views on how mechanistic studies have swiftly translated into powerful targeted therapies in two recent clinical studies that led to the FDA approval of selpercatinib for certain tumors in which RET is altered.

The risks posed to patients with cancer by the current COVID-19 pandemic demand rapid structural changes in healthcare delivery, with many positive changes likely to continue long term. An immediate critical reassessment of trial methodology based on clinical and scientific priorities is essential to ensure the resilience of clinical cancer research and optimize patient-centered care.

Zhai et al. identify clinical brain-penetrant BACE1 inhibitors as regulators of macrophage-dependent phagocytosis in glioblastoma through IL-6–STAT3 signaling and demonstrate preclinical therapeutic efficacy in orthotopic mouse models and PDXs.

Sarry and colleagues demonstrate that adaptive resistance to venetoclax + cytarabine therapy in acute myeloid leukemia relies on mitochondrial respiration and show that combination with electron transport chain complex inhibitors delays relapse in patient-derived xenograft models in vivo.

Durocher and colleagues identify CIP2A through synthetic lethal CRISPR screens as a key regulator of adaptive feedback mechanisms controlling chromosomal stability arising from accumulated DNA lesions in BRCA-mutated tumor cells.

Kang and colleagues identify a specific compound blocking MTDH1–SND1 interaction, which prevents metastatic breast cancer progression, induces regression of established metastasis in preclinical models and restores chemosensitivity.

Straussman and colleagues undertake clonal analyses and show that drug tolerance to EGFR therapy in lung cancer cell populations is an inherited continuous trait that is determined by IRS1 phosphorylation.

Yarchoan and colleagues present a single-arm phase 1 clinical trial of cabozantinib with immune checkpoint inhibition for patients with hepatocellular carcinoma. Using high-dimensional spatial analysis, they identify immune features enriched in responders.

Pappalardi and colleagues identify a potent noncovalent DNMT1-selective inhibitor with improved tolerability and efficacy in preclinical AML models compared with clinically validated covalent pan-DNMT inhibitors.

Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell–instructed, immune-evasive tumor microenvironment.

D’Andrea and colleagues identify the antibiotic novobiocin as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors in vivo, including these with acquired PARP inhibitor resistance.

Poulikakos and colleagues demonstrate that thermostable CDK6 complexes promote resistance to therapeutic targeting of CDK4/6 in cancer.

Yang and colleagues perform a network system–pharmacology approach and clinical data integration, and identify LCK and BCL2 signaling as the molecular determinants of dasatinib response in pediatric and adult patients with T-ALL.

Zender, Dauch and colleagues demonstrate that pharmacologically induced lipotoxicity by activating LXRα and Raf-1 inhibition provides a metabolic therapeutic strategy for hepatocellular carcinoma.

Alonso and colleagues develop immune-stimulating antibody conjugates capable of specific delivery of TLR7/8 agonists to tumors, which induces durable antitumor immunity.

Amgalan et al. identify BAX as a therapeutic target to prevent chemotherapy-induced cardiotoxicity without affecting the antitumor properties of doxorubicin.

Rossjohn, van der Vliet and colleagues develop single-domain antibodies binding composite CD1d and NKT T-cell receptor antigens, inducing specific antitumor immune subsets.

Bhardwaj et al. report that adding Flt3 ligand to the treatment strategy effectively increased DC populations and increased T-cell responses in a randomized phase II trial of a DC-targeted vaccine for the melanoma antigen NY-ESO-1.

Quezada and colleagues develop improved anti-CD25 antibodies that preserve IL-2 signaling and enhance single-agent antitumor immunity and immunotherapy through specific and efficient T_reg cell depletion.

Stewart et al. use circulating tumor cell-derived xenografts from patients with small-cell lung cancer to study tumor heterogeneity following the onset of therapeutic resistance.

Zhang and colleagues report that targeting GLS1 alleviates the glutamine dependence of ARID1A-mutated ovarian clear cell carcinomas, thereby suppressing their growth.

Ma et al. apply few-shot learning to train a neural network model on cell-line drug-response data, and they subsequently transfer it to distinct biological contexts including different tissues and patient-derived tumor cells and xenografts.

Ishikawa and colleagues perform integrated genomic and drug-sensitivity screens with extensive PDX modeling and reveal combined XIAP and BCL2 inhibition as a vulnerability hub across AML genetic alterations.

Eilers and colleagues report that Aurora-A suppresses transcription–replication conflicts in MYCN-driven neuroblastoma, a vulnerability that can be targeted with a combination of Aurora-A and ATR kinase inhibitors.

Zhang and colleagues analyzed data from patient samples exposed to the BCL2 inhibitor venetoclax, approved for treatment of acute myeloid leukemia, identifying modes of therapy resistance and synthetic lethality with MCL1 inhibition.

Ferrando and colleagues analyze matched diagnostic and relapsed acute lymphocytic leukemia by whole-genome sequencing, and perform in vitro genome-wide CRISPR screens, to examine alterations associated with chemotherapy resistance.