Clinical trial of triple therapy provides valuable clues about lung cancer transformation and drug resistance

In a new clinical trial, researchers have interrogated how patients with an aggressive form of lung cancer respond to treatment with a triple combination therapy. Although the therapy didn’t prevent disease progression or transformation in many of the patients, the results nevertheless provide valuable data about how tumor plasticity drives treatment resistance. Approximately 20% of lung cancers have mutations in the gene EGFR, and researchers have developed drugs such as osimertinib that target mutant EGFR to treat metastatic disease. The drug is often effective at first, but patients usually develop treatment resistance for various reasons, including further mutations or histological transformation. The latter occurs when tumor cells acquire new properties or even shift to a different cancer type, such as transforming from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC). These transformations often enhance the cancer’s aggressiveness and capacity to resist treatments, so new therapeutics are urgently needed. Here, Lena Morrill Gavarró and colleagues theorized that combining osimertinib with platinum and etoposide chemotherapy could prevent the transformation of EGFR-mutant LUAD into SCLC. They gave the combination therapy to 11 patients with EGFR-mutant LUAD who had a high risk of transformation due to possessing mutations in two other genes named TP53 and RB1. Five of the patients still experienced transformation to SCLC, and the median progression-free survival was 11 months. Genomic and single-cell analysis revealed that mutations in TP53 and RB1 were major drivers of tumor plasticity and transformation, and that osimertinib may have even accelerated the cancer cells’ plasticity. “These findings have deep implications for developing strategies to predict, prevent, or therapeutically target plasticity-mediated resistance,” the authors conclude.