According to recent figures published by the Spanish Society of Medical Oncology (SEOM), in 2023 more than 30,000 new cases of lung cancer will be diagnosed in Spain alone, making it the second most frequent type of cancer in that nation. In addition to its high prevalence, its five-year survival rate is one of the lowest of all cancers. It is the cancer with the highest mortality.
One of the great advances in cancer research in recent decades has been the development of personalized therapies, which target the specific biology of each type of tumor. Their success is due to the fact that they act on specific genes and proteins involved in the growth and survival of cancer cells. Taking into account that a quarter of lung cancers have a mutated KRAS gene, personalized therapies against this gene would represent a great advance in the treatment of patients with lung cancer. In fact, in 2021, the first personalized drug (Sotorasib) was approved in the United States, targeting the most frequent KRAS mutation in lung cancer, which is a direct consequence of smoking. Specifically, Sotorasib inhibits the KRASG12C mutant isoform. However, there is a problem, most lung cancer patients quickly develop resistance to the drug and the treatment is no longer effective.
Research reveals the mechanisms by which lung cancer patients develop resistance to Sotorasib
The study is the work of specialists from the National Cancer Research Center (CNIO) and the Cancer Research Center (CIC) (attached to the Higher Council for Scientific Research), all of these institutions in Spain.
The study, in which the group led by Matthias Drosten, a CICANCER researcher, and the CNIO’s Experimental Oncology group led by Mariano Barbacid have collaborated, also shows that, if the KRAS oncogene could be completely inhibited by more potent drugs or by degraders , the resistances observed in the clinic could be eliminated.
The group led by Drosten studies how resistance to Sotorasib arises in order to prevent it by developing improved strategies. To do this, it uses genetically modified mouse models, with activating mutations in KRAS and other mutated genes, and develops aggressive tumors similar to those of humans. “We have seen that one of the best strategies to treat these tumors is to inhibit KRAS. We have verified tumor regression and cure in all cases when the mutated KRAS gene is completely eliminated”, highlights the CSIC scientist.
On the other hand, it has been shown that resistance occurs because tumors can quickly adapt to the presence of the inhibitor. And in response to treatment, lung tumor cells increase copies of the KRAS gene. In addition, this study has detected a second cause that explains resistance to the drug and the decrease in its activity: transcriptional programs (which allow the conversion of DNA into RNA) are activated that increase the chemical modification of drugs. “These mechanisms studied in the mouse are also present in some human tumors. Therefore, the results of this research can help to identify new forms of treatment adapted to each patient”, points out Marina Salmón, first author of the paper and CNIO researcher.
Sotorasib-resistant lung cancer cells carrying multiple copies of the mutated KRAS gene (in red). (Image: CIC)
A door to the design of new personalized treatments
This research opens the door to the design of new personalized treatments based on two pieces of evidence. On the one hand, it has been found that tumor cells with gene amplifications lose their fitness when they are no longer exposed to the inhibitor, which could help define new treatment guidelines. On the other hand, other drugs can be directed to other molecules, such as the NF-kB and STAT3 proteins, also identified in this study as possible mediators of resistance in lung tumor cells. In case resistance is detected through NF-kB and STAT3, inhibitors against these molecules are likely to be effective in reversing resistance.
As a wide variety of resistance mechanisms have been identified, patients with lung cancer who have the KRAS mutation and who do not respond to treatments should undergo a personal analysis to detect what type of resistance the cells have developed and to be able to adapt the treatment . Another challenge that emerges from the results of this research, and that would help increase survival in lung cancer, is based on being able to develop a therapy similar to the complete elimination of the KRAS oncogene from cancer cells.
Ultimately, Drosten points out, “this research should encourage other researchers and the pharmaceutical industry to continue developing new targeted therapies against KRAS.”
The study is titled “KRAS oncogene ablation prevents resistance in advanced lung adenocarcinoma”. And it has been published in the Journal of Clinical Investigation. (Source: CIC / CSIC)