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Final Report Summary - KRASMIR (The role of miRNAs in KRAS-driven Non-Small Cell Lung Cancer)

Lung cancer (LC) tops the list of deaths by cancer in developed countries. Tobacco exposure, environmental agents and genetic factors can transform normal lung cells into malignant cells by activating key genes that favor cell proliferation. The paradigm of these genes is KRAS. Perturbation of KRAS triggers an abnormal network of effector signals responsible for LC development. KRAS is most commonly mutated in LC and epitomizes a unique therapeutic target, a sort of “Holy Grail”, that has been the focus of intense research. However, KRAS oncogene has remained “undruggable” to date. Therefore, this project will investigate novel effectors in KRAS mutated LC that could provide mechanistic insights for new opportunities of therapeutic intervention.
MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional regulators of mRNA target genes, and have been involved in a plethora of biological functions. Our preliminary results unveiled effector miRNAs required for KRAS oncogene function. In the original proposal we proposed a series of Objectives to investigate the role of these miRNAs in mutant KRAS-driven lung tumorigenesis:
Objective 1. To study the role of miR-181ab-1 cluster in vivo and the potential therapeutic value of miR-181a and b using a genetically-modified mouse model of Kras-driven lung cancer.
The experiments achieved in Objective 1 were aimed to define the molecular and therapeutic role of the miR-181ab1 cluster in mutant Kras-driven lung cancer. To this, several models to address the chemopreventive (Subaim 1.a) and therapeutic (Subaim 1.b) role of this cluster were developed and investigated.
Subaim 1.a. The functional role of miR-181ab1 cluster in lung tumor initiation and progression.
Subaim 1.b. A pre-clinical mouse model to test the therapeutic potential of KRAS suppression through miR-181a/b inhibition.
Objective 2. To investigate the functional role of miR-181a/b in human KRAS-driven oncogenesis using NSCLC cell lines and primary lung epithelial cells.
This objective was aimed to test the pro-oncogenic and transforming effects of the members in the miR-181ab1 cluster specifically in lung cancer cell lines (outside the microenvironment context).
Subaim 2.a. The role of miR-181a/b in Kras-dependent oncogenesis and transformation in vitro.
Subaim 2.b. The role of miR-181a/b in human lung cancer tumorigenesis.
Objective 3. To identify miR-181a/b-regulated genes functionally critical for KRAS-dependent lung cancer.
This object was aimed to unveil miR-181ab1 target genes that may have a functional role in mutant KRAS-driven oncogenesis which may explain at the molecular level the over phenotype derived from miR-181ab1 loss.
Subaim 3.a. Identification and validation of miR-181a/b direct targets.
Subaim 3.b. Functional validation of miR-181a/b targets in vitro and in vivo.
Objective 4. To evaluate the clinical implication of miR-181a/b-regulated genes in human NSCLC: translating in vitro and in vivo findings to human patients.
In this Objective we assessed the clinical role of the miR-181ab1 targets identified in Objective 3 that could represent markers of lung cancer disease in the context of mutations in KRAS and could serve as a biomarkers of disease progression.
Subaim 4.a. In silico characterization of miR-181a/b-regulated genes in data sets of NSCLC patients.
Subaim 4.b. Evaluation of NSCLC specimens to determine the expression of miR-181a/b and miR-181a targets.

In the course of this project, we have observed that inhibition of these miRNAs decreased cell proliferation and organoid growth in 2D and 3D culture systems respectively. Notably, their ablation in vivo decreased tumor burden and increased overall survival of mice. Moreover, ablation of these miRNAs in established tumors prevented tumor growth. More recent analyses unveiled a gene signature of miRNA target genes whose expression as a whole is associated with patient prognosis. This gene signature includes direct targets of the investigated miRNAs that provide the mechanistic explanation for the over phenotype observed upon deletion of the miRNAs. Collectively, these findings point at a strong functional and clinical role of these miRNAs in KRAS-driven LC and supports further work to develop therapeutic tools to target these miRNAs as well as to address the role of themiRNAs in other mutant KRAS-driven tumors.

The results obtained within the scope of the ended project are in tune with the overall priority of this proposal to obtain a better understanding of lung cancer biology and to provide the opportunity to uncover functionally and clinically relevant genes in lung cancer. The recent discovery of KRAS-regulated miRNAs offers a unique opportunity to unveil novel mechanistic insight relevant to circumvent these problems by targeting downstream effectors. Given the limited armamentarium against lung cancer and the lack of data on this topic, the results clearly have a socio-economic impact.
Social and economic considerations
The proof-of-concept provided by this study on the importance of the studied miRNAs in lung cancer tumors driven by mutant KRAS has a marked social impact as it opens up the possibility for the development of alternative therapeutic tools based on the inhibition of miRNAs in a group of patients (mutant KRAS lung cancer patients) which is generally refractory to both conventional chemotherapy and targeted therapies.
The transfer of knowledge to the industry setting could generate economical benefits derived from the commercial exploitation of such therapeutic tools. Additionally, on the long term, an effective treatment of lung cancer patients with mutations in KRAS would decrease the economical impact related to the hospitalization and treatment of patients with a largely incurable disease.
Scientific and technical considerations
The main impact of the project in this regard is the identification of these miRNAs as an oncogenic dependency in lung tumors with KRAS mutations, as well as the development of new experimental models (genetically-engineered mouse models, cell lines and 3D organoid systems).
The knowledge obtained from this study has allowed us to establish collaborations to study the effect of these tumors in other tumors where KRAS is mutated, such as pancreatic cancer, another deadly disease for which the therapeutic armamentarium is limited. The data generated in the framework of this collaboration suggest that this cluster is also critical for the development and maintenance of these highly aggressive tumors, what opens up a new line of research for the future.

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