NCI-funded Acquired Resistance to Therapy Network (ARTNet) Works to Understand the Mechanistic Basis of Acquired Resistance to Cancer Therapies and Disease Recurrence

ARTNet bridges basic science discoveries to preclinical testing to translate therapeutic strategies and overcome cancer therapy resistance

Background on Cancer Therapy Resistance

Most tumor types develop resistance to anti-cancer therapies, which is linked to approximately 90% of all cancer-related relapses and mortality. Tumors can acquire therapy resistance through adaptive changes following cancer treatment. These changes involve interacting genetic, non-genetic, and stromal processes across the tumor-tumor microenvironment continuum, including:

• Genetic and epigenetic changes
• Stromal remodeling
• Metabolic reprogramming
• Upregulation of drug efflux transporters
• Loss of target or adaptations to bypass targeted pathways
• Enhanced capacity for cellular and stromal plasticity driving heterogeneity

A Major Challenge

Researchers do not fully understand the mechanisms involved in acquired therapy resistance.

• Cancer and stromal cells within a tumor ecosystem exist in an unlimited continuum of heterogeneity, which poses challenges for cancer treatment.
• A poorly understood and complicated mixture of cellular and stromal diversity and adaptive properties in both compartments contribute to acquired therapy resistance.
• Although precision oncology approaches can match molecularly targeted therapies based on the mutations in a patient’s tumor, they often fail to anticipate acquired therapy resistance emerging from cells that are not necessarily mutant and influenced by microenvironmental responses.
• Research on resistant tumors and appropriate models in the setting of disease recurrence is limited.

Recently Launched ARTNet Will Focus on Acquired Resistance

In 2022, NCI funded the Acquired Resistance to Therapy Network (ARTNet Website; RFA-CA-21-052, RFA-CA-21-053), which will focus on the mechanisms of acquired resistance to cancer therapies and disease recurrence and integrate those findings through team science. This new program is building and expanding on the progress of the Drug Resistance and Sensitivity Network (DRSN) that focused on understanding traditional pathways and mechanisms of drug resistance in cancer. The DRSN was launched through the Cancer Moonshot and funded by the 21st Century Cures Act.

ARTNet’s Goals

• Team science that bridges basic, preclinical, and translational research
• Testing hypotheses on the biological basis of resistance in clinically relevant model systems
• Providing evidence along the shared tumor-tumor microenvironment continuum to inform new strategies that can be better translated into future clinical trials
• Unifying “Center-based” approach where a central scientific theme focused on addressing challenges in acquired resistance and disease recurrence defines the projects
• Supporting projects represent a range of treatment modalities (e.g., chemotherapy, radiation, targeted agents, immunotherapies, combined modalities), cancer type(s), and novel mechanisms to address questions and barriers in acquired therapy resistance
• Generating novel and actionable translational strategies that are informed by the tumor-tumor microenvironment as co-organizers research models

ARTNet Structure and Members

The ARTNet consists of five research centers and a coordinating-data management center that are examining cancer types where acquired resistance and disease recurrence pose significant obstacles (e.g., cancers of the lung, esophagus, head-and-neck, pancreas, and leukemia). The investigative teams will coordinate to use state-of-the-art approaches that combine -omics, imaging, immunology, stromal, and cancer cell biology modeling.

PI(s)/Institution	Center Title/Project Information
Alan Hutson (contact); David Goodrich; Song Liu; Martin Morgan/Roswell Park Cancer Institute Corporation	Coordinating and Data Management Center for Acquired Resistance to Therapy Network
Trever G. Bivona (contact); Jack Roth/University of California, San Francisco	Bay Area & Anderson Team against Acquired Resistance — U54 Program (BAATAAR-UP)
Boyi Gan (contact); Albert Koong/University of Texas MD Anderson Cancer Center	Acquired Resistance to Therapy and Iron (ARTI) Center
Pankaj Singh/University of Nebraska Medical Center	Pancreatic Cancer ARTNet Center
Jeffrey Myers (contact); Vlad Sandulache/University of Texas MD Anderson Cancer Center	The Houston Center for Acquired Resistance Research (H-CARR)
Jeffrey Tyner (contact); Brian Druker; Shannon McWeeney/Oregon Health & Science University	Architecture and Trajectory of Acquired Resistance to Therapy in AML

For further information on ARTNet, contact Michael Espey, PhD, Division of Cancer Treatment and Diagnosis (sp@nih.gov) or Jeffrey Hildesheim, PhD, Division of Cancer Biology (jeff.hildesheim@nih.gov).