Many lung cancer patients are genetically tested for EGFR mutations, and these patients can often control their tumours with EGFR-targeted drugs. Although targeted drugs are effective and have fewer side effects than chemotherapy, resistance to them inevitably occurs, after which they are no longer effective.
Recently, researchers at MD Anderson Cancer Center, a leading global cancer specialist, have identified a new therapeutic target, CD70, that specifically targets EGFR-mutated non-small cell lung cancer (NSCLC) resistant cancer cells, and it is claimed that treating this target could eliminate drug-resistant cells that remain after EGFR-targeted therapy. The study was published in Cancer Cell.
This preclinical study was led by Dr Monique Nilsson and Dr John Heymach (Chair of Thoracic/Head and Neck Medical Oncology). The researchers found that CD70, a cell surface protein that can normally be found on immune cells, is highly overexpressed in cancer cells that remain after treatment with EGFR-targeting drugs.
The researchers confirmed that in laboratory models, CD70 can be effectively targeted for use in cutting-edge antibody-coupled drugs (ADC drugs) or cellular immunotherapy.
"Cancer cells that remain after targeted therapy are essentially a reservoir in which future drug-resistant cancer cell assortments will eventually evolve out and grow," Heymach said. "These findings lay the groundwork for us to provide effective therapies against that target, using drugs that target CD70 to eliminate residual cancer cells after targeted therapy."
Approximately 10-15% of patients with non-small cell lung cancer carry an EGFR mutation. While treatment with EGFR-targeted drugs (such as oxitinib) effectively kills most cancer cells, a small number of drug-resistant cancer cells remain. These cells can remain dormant or even undetected for long periods of time, but they assemble and eventually grow and metastasise quietly.
Cancer cells can become resistant to EGFR-targeted drugs through a variety of mechanisms, including, for example, epithelial-to-mesenchymal transition (EMT). Tumours that undergo EMT can become resistant to most known drugs, leading to a poor prognosis for patients with recurrent tumours, and therefore there is a far from unmet need for patients to address the issue of drug resistance.
Further studies have shown that CD70 overexpression is significantly upregulated in drug-resistant cells that remain after targeted therapy.
"The finding that CD70 is upregulated in lung cancer cells at an early stage of resistance evolution is really encouraging, as it means we can target these cells for treatment quickly, rather than having to wait for them to complete full drug resistance," Nilsson said.
Based on this discovery, the researchers later confirmed the validity of this idea with ADC drugs targeting CD70, CAR-T therapy, and CAR-NK therapy, and they successfully eliminated drug-resistant residual cancer cells in laboratory models.
While this study was limited to the context of lung cancer, CD70 overexpression is also present in many different cancer types such as breast, pancreatic, ovarian, kidney and melanoma.
"We believe that what has been learned from the problem of resistance to EGFR-targeted drugs in lung cancer may be more broadly applicable to other cancers that are resistant through the EMT mechanism," Heymach said.
Such CD70-based therapeutic strategies are currently in clinical trials for other cancers as well, so let's wait and see.
