A subpopulation of cancer cells characterized by the aggressive mutated K-RAS gene, so far pharmacologically untargetable, has been identified by using a new technique. The study led by Cnr-Itb and published on Communications Biology, demonstrates the efficacy of a novel drug treatment
Lung cancer is the leading cause of cancer death, and it is responsible for approximately one third of all cancer deaths. Despite enormous scientific advances, treatment options are currently still limited. An international research group, led by Elena Levantini from the Institute of Biomedical Technologies of the National Research Council (Cnr-Itb) of Pisa, where she coordinates the Molecular Oncology Laboratory, and who also holds research positions in the Hematology/Oncology department of the Harvard Medical School-affiliated BIDMC hospital in Boston, contributed a new study on a novel drug. Such treatment is capable of decreasing tumor growth in preclinical studies on a murine model of lung cancer carrying mutated K-RAS genes. The study, that also involved the Cancer Science Institute of Singapore, is published in Communications Biology.
"We have developed an important innovative methodology based on single-cell RNA sequencing, also known as high-resolution transcriptomics - explains Levantini - which allowed us to identify the entire transcriptome (set of RNA) present in each lung tumor cell. Through our experiments, we have identified important marker genes that allow us to identify tumor cells specifically present in the subtype of tumors caused by mutations in the K-RAS oncogene and to attack them with a new drug". This molecular subtype affects 10-30% of patients with non-small cell lung cancer and has so far been considered untreatable as no drug therapy has yet been approved for the vast majority of K-RAS mutant tumors. Lung cancer represents an important subject of study not only due to the high percentage of clinical cases and the high frequency of relapses, but also because it is necessary to have appropriate preclinical models on which to study it in details. Our experimental platform made it possible to identify and compare different subtypes of tumor cells, both in the experimental model used in the study, and in lung neoplasms taken from patients, highlighting important cell subpopulations conserved between humans and the mouse model. "Having identified a specific population of tumor cells conserved in the two species and present only in tumors positive for the mutant K-RAS oncogene, and absent in healthy lung cells - says Levantini - we tested in the mouse model, that acts as an avatar of human pathology, a therapy aimed at eliminating cancer cells.
In particular, we counteracted the evolution of lung cancer by using a new drug that inhibits the activity of the BMI1 oncogene. The drug is currently in clinical trials in the United States. This is an important step, given that in order to improve patients’ survival it is necessary to identify the molecular networks involved in tumorigenesis and consequently produce new drugs directed against these molecular targets (the so-called molecular or personalized therapy). In other words, rather than resorting to generalized chemotherapy, which does not go against a specific gene, we are going to treat this subtype of cancer cells with a targeted drug". Currently, most patients receive generalized chemotherapy treatments, aimed at attacking tumor cells; however, such treatments do not specifically target the specific molecules involved in the tumor process and they can also cause damage to healthy cells. "Until we are able to decipher the complexity of the cell subpopulations contained within the tumor mass, we will not be able to design targeted treatment options capable of decreasing the number of patients that experience tumor recurrence," emphasizes the researcher.
CNR - Istituto di tecnologie biomediche
Gaetano Massimo Macrì
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