Unveiling Chemotherapy Resistance in Lung Cancer

New Insights from Comprehensive Tumor Analysis

Small cell lung cancer (SCLC) is a particularly aggressive lung tumor mainly found in heavy smokers. Most patients are treated with chemotherapy in order to counteract the rapid proliferation of the tumor. This results often in notable efficacy against the tumor, however, relapses are frequent over time. To understand the exact development of tumors in individual patients during treatment and relapse is a significant challenge and goal. 
In a comprehensive research endeavor, scientists of the e:Med alliance InCa led by Professor Dr. Roman Thomas (University of Cologne) delved into the development of tumors throughout treatment regimens. They identified distinct populations of tumor cells that respond disparately to chemotherapy in the initial stages of the illness and subsequent treatments as the disease progresses.
“When the tumor returned - which occurs in almost all patients - a different dominant cell population was usually found. With further treatments during the course of therapy, for example with radiation, the cancer cells showed characteristics of the genetic damage caused by the first chemotherapy”, summarizes Professor Dr. Julie Goerge (University of Cologne), first author and leader of the study, the sobering but important novel observation. 
By employing multi-region sequencing of 160 tumors from 65 patients, the team traced tumor development from diagnosis through chemotherapy and immunotherapy. They discovered that the effectiveness of therapy early on is largely attributed to prevalent populations of treatment-sensitive cancer cells present at diagnosis. Additionally, they found that these dominant sensitive cell populations mask other diverse cancer cells, originating from early precursors, which are resistant to treatment and proliferate unchecked post-successful treatment. These cancer cells reveal genetic alterations reflective of the damage caused by initial chemotherapy. The researchers identified specific genetic characteristics within tumor cells associated with resistance to chemotherapy.
The study's findings suggest that cancer genome alterations not only drive malignant transformation in SCLC but also influence the clinical phenotypes of chemotherapy sensitivity, tumor progression and relapse. The efficacy of future treatment developments may be hindered by the number of therapy-resistant tumor cells. Therefore, one potential therapeutic approach could involve administering intensive initial treatment to minimize the emergence of resistant cancer cells later on. 

Original Publication: www.nature.com/articles/s41586-024-07177-7