New targets for the treatment of lung cancer

Scientists from the Autonomous University of Madrid (UAM) and the Puerta de Hierro Majadahonda University Hospital have shown that mitochondrial proteins offer very advantageous therapeutic targets for the treatment of lung cancer. The results, published in Oncogenesis , show that therapies targeting metabolic markers in the mitochondria significantly prolong the life of mice.

Despite the great advances and success of therapies targeting oncogenes and immune checkpoint inhibitors, lung cancer is today the leading cause of death worldwide.

It was known that the proteins that control the metabolic reprogramming that tumors undergo to favor their growth and spread to other tissues (metastasis) can also be targets of antitumor therapy. However, to date the detailed expression pattern of the metabolic enzymes of lung adenocarcinomas (ACP) was unknown, which prevented the development of therapies directed against these enzymes.

Now, a study published in the journal Oncogenesis has quantified the changes that occur in the expression of thirty metabolic proteins in 128 biopsies of ACP and adjacent non-tumor tissue, using the Reversed-Phase Protein Array immunological technique of the platform PROTEOmAb.

When evaluating the prognostic value of the changes produced in these enzymes of the tumor tissue, the researchers have shown that the enzymes of the oxidation of fatty acids, oxidative phosphorylation and the antioxidant response -the vast majority of mitochondrial proteins- are independent prognostic factors of survival and/or disease recurrence.

Specifically, since in the proteomic signature that predicts metastasis, IF1 overexpression in carcinoma appears as a marker of good prognosis, researchers have studied the possible mechanisms underlying this phenotype.

IF1 is the physiological inhibitor of the mitochondrial enzyme that synthesizes ATP (adenosine triphosphate), the energy currency of the cell. Therefore, it promotes its inhibition and an increase in glycolysis in the tumor.

Although a priori this increase in glycolysis could cause increased proliferation, this is not the case. The work shows that IF1 overexpression prevents metastatic disease by favoring a less invasive phenotype and a greater vulnerability of the tumor cell to different death stimuli.

proof of concept

The study —led by Prof. José M. Cuezva at the Sevecho Ochoa Molecular Biology Center (CBMSO-UAM/CSIC), Hospital 12 de Octubre Research Institute (i+12/UAM) and U713 of the CIBER for Rare Diseases (CIBERER-ISCII)—was completed with a proof of concept using mitochondrial proteins as the therapeutic target of ACP.

Laura Torresano Cicuéndez, first author of the article, explains that as part of the test "the therapeutic value of inhibitors of the assimilation or oxidation of fatty acids approved by the FDA, in combination with cisplatin (conventional treatment of ACP) and nebivolol”.

The latter, as recently demonstrated by the same group in Nature Communications , is a β-blocker that has a potent antitumor effect in vivo , since it inhibits the bioenergetic function of the mitochondria.

"With this approach -concludes the researcher- we were able to demonstrate that therapies directed at metabolic markers of the mitochondria significantly prolong the life of the mice and provide them with greater well-being, compared to conventional cisplatin treatment".

Image: In red, increased glycolysis (GAPDH, SUVmax) and mitochondrial antioxidant response (SOD2, PRX3) are markers of poor prognosis for patients with PCA. In green, a higher oxidation of fatty acids (CPT1, ETFA, HADHA), of the cytoplasmic antioxidant response (PRX6) and a lower activity of oxidative phosphorylation (IF1) predict a good prognosis for patients. The prominent role of FA β-oxidation and mitochondrial oxidative phosphorylation as targets for more effective and less harmful ACP therapy is shown to the right of the image / Torresano et al.

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Bibliographic reference:

Torresano, L., Santacatterina, F., Domínguez-Zorita, S., Nuevo-Tapioles, C., Núñez-Salgado, A., Esparza-Moltó, PB, González-Llorente, L., Romero-Carramiñana, I. , Núñez de Arenas, C., Sánchez-Garrido, B., Nájera, L., Salas, C., Provencio, M., Cuezva, JM 2022. Analysis of the metabolic proteome of lung adenocarcinomas by reverse-phase protein arrays ( RPPA) emphasizes mitochondria as targets for therapy . Oncogenesis 11:24.