Volume 2 Issue 5, May 2021

The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drugs. However, immunotherapy combinations have shown promising activity, targeted chemotherapy options via antibody–drug conjugates are in the clinic, and molecular means of identifying targetable subsets are on the horizon. This Clinical Outlook discusses current and future possibilities for treating triple-negative breast cancer.

Mutations in genes encoding epigenetic modifiers are frequent in acute myelogenous leukemia (AML) and have been proposed to cause AML via activation of oncogenes and repression of tumor suppressors. Two studies now identify unexpected oncogenic mechanisms and therapeutic vulnerabilities in AML arising from mutations in genes encoding the epigenetic regulators DNMT3A and ASXL1.

Two recent studies demonstrate how autophagy, in both tumor cells and host tissues, regulates anti-tumor T cell responses. These works add to accumulating evidence that inhibitors of autophagy could be used in combination with immunotherapy in certain cancer types.

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

Brastianos and colleagues report interim trial results on the intracranial clinical benefit of palbociclib for patients with progressive metastatic brain cancer carrying cyclin-dependent kinase pathway alterations.

Wong and colleagues show that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, and propose dual targeting of ULK1 and PD-1 for these tumors.

Shilatifard and colleagues demonstrate gain-of-function mutations in ASXL1 that drive BAP1 stabilization and widespread epigenetic changes in myeloid neoplasms, and develop a chemical inhibitor with therapeutic potential for ASXL1-altered leukemia.

Müller-Tidow and colleagues demonstrate that hotspot DNMT3A mutations found in clonal hematopoiesis and acute myeloid leukemia render cancer cells sensitive to the DNMT1 inhibitor azacitidine through focal DNA demethylation, viral mimicry and interferon activation.

Quail and colleagues demonstrate that neutrophil-derived ROS and extracellular traps (NETs) mediate breast cancer metastasis to the lungs by altering endothelial junctional adhesions, thus favoring vascular permeability and transendothelial migration of cancer cells.

Robbins and colleagues develop and test a machine learning neoantigen ranking model using experimentally validated neoantigens from human tumors, providing a resource of targetable neoantigens for future immunotherapies.