Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons. In their Review, Shaw and colleagues provide a comprehensive picture of the various pathological mechanisms involved in this complex disease, and discuss the deep and diverse pipeline under development to tackle these processes. They highlight advances in ALS translational research that might be broadly applicable to other neurodegenerative disorders.

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.

The potential of therapeutically targeting phosphoinositide kinases (PIKs) beyond the class I PI3Ks is increasingly being realized. Here, Burke et al. describe the structure, function, regulation and roles in disease of all clinically relevant PIKs outside of the class I PI3Ks, assessing potent and specific small-molecule inhibitors in development.

The discovery of the monoclonal antibody trastuzumab almost 25 years ago revolutionized treatment and drug development for HER2⁺ breast cancer. Here, Swain et al. review the current standard of care for HER2⁺ breast cancer, describe mechanisms of drug resistance and focus on next-generation platforms and therapies for the treatment of this disease.