Research
Oncogenic pathways in lung cancer : A. Maraver

Lung cancer kills every year around 2 million people in the world being a significant public health concern. Thanks to the development of new therapeutic options as targeted therapy or immune check point inhibitors, in the last years the mortality decreased, but only mildly, due to resistance to treatments, both intrinsic and acquired.

The main goal of our laboratory is to avoid or at the very least delay the appearance of resistance to the main treatments provided to lung cancer patients in the clinic today. The diagram depicts our scientific strategy for each of the treatments under study and implies a bed to bench and bench to bed approach thanks to the strong synergy with our local cancer hospital, ICM. Besides clinical oncology, our complementary approaches involved: 1) understanding the role of the tumor microenvironment, 2) what forms the residual disease, 3) revealing the molecular mechanisms behind resistance, 4) and the use of a plethora of preclinical models to test for innovative treatments paving the way for clinical trials at ICM, our major final goal in the lab.

Axis 1: Mechanisms of intrinsic and acquired resistance to Chemotherapy (project leader H. Tourriere, CNRS staff scientist)

In lung cancer chemotherapy is mainly based in platinum therapies and most of the patients will benefit from them as some line of treatment. Even though platinum-compounds display an initial effect on these patients, the onset of the relapse constitutes the main challenge for the clinic, thus it is fundamental to understand them in order to improve survival of patients. 

We recently demonstrated that upon carboplatin treatment, the Notch pathway is activated through DNA damage response activity, and upon showing that it was mediated by a non-degradative activity of MDM2, we showed that combining the inhibition of both MDM2 and Notch pathway, we abolished the resistance against carboplatin in lung cancer in vivo (https://doi.org/10.1101/2024.04.29.591624). At the moment we are further exploring how Notch activation contribute to chemoresistance (i.e., via modulation of nucleotide metabolism, epigenetics markers, DNA repair) to identify new targets in chemoresistance.

Axis 2: Enhancing the deep of response to EGFR inhibitors (project leaders D. Bracquemond, PhD student and M. Mancini, INSERM staff scientist)

EGFR was the first oncogene with targeted therapy in lung cancer. While little by little the survival of patients is increased thanks to the appearance of new generation of molecules, still majority of patients develop resistance. We uncovered that acquired resistance to first generation EGFR inhibitors can be eliminated by co-treatment with inhibitors of the Notch pathway (https://doi.org/10.1172/JCI126896). More recently, we also targeted the tumor residual cells, or the so-called drug tolerant persister cells, by co-inhibition of the Notch pathway and EGFR using the clinical molecules Nirogacestat and Osimertinib respectively, and observed a massive increase in survival using clinically relevant preclinical models. The molecular dissection of this interesting phenotype is providing us new targets to increase the therapeutic benefit of EGFR inhibitors in lung cancer patients with the concomitant increase in patients’ life expectancy.

Axis 3: Hampering KRAS signaling pathway (project leaders Q. Thomas, ICM oncologist, PhD student and X. Quantin, ICM oncologist)

KRAS was considered undruggable until very recently and strategies were focused into downstream pathways used by KRAS. Among those pathways, our lab was the first demonstrating the key role of the Notch pathway in KRAS-driven lung cancer (https://doi.org/10.1016/j.ccr.2012.06.014). More recently and using organoids derived from KRASG12C-driven lung cancer PDX we demonstrated that the Notch pathway increase the potency of KRASG12C inhibitors and can tackle resistance against these inhibitors in vivo. Finally, we are performing at the moment a clinical trial to monitor Notch pathway activity in lung cancer patients treated with KRASG12C inhibitors (https://www.icm.unicancer.fr/fr/essais-cliniques/adenocarcinome-pulmonaire-egfr-kras-g12c-inhibiteurs-de-tyrosine-kinase-resistance). 

Axis 4: Uncovering the vulnerabilities of MET oncogene (project leaders L. Brunet, postdoc and M. Mancini, INSERM staff scientist)

MET oncogene plays a major role in EGFR inhibitors resistance but also is an important driver oncogene. Due to the lack of preclinical models, our knowledge in this oncogene is limited compared to other important lung cancer oncogenes. To fill this gap, we recently developed several preclinical mouse models to understand both the MET-induced resistance against EGFR inhibitors (https://doi.org/10.3390/cancers13143441) and the MET-driven lung cancer biology (Brunet et al, manuscript in preparation). Thanks to these in vivo models unique to our laboratory, we are understanding the role of MET in the tumor immune microenvironment (see axis 6) and uncovered an Achilles’ heel for MET-driven lung cancer under patenting by Inserm-transfert.  

Axis 5: Targeting the lung cancer epigenetic landscape (project leader E. Fabbrizio, CNRS staff scientist)

It is well known that oncogenic signaling induces massive changes in transcription of cells, but the 3D chromatin changes associated with them are largely unknown in lung cancer. To shed light into this interesting phenomenon we generated oncogenic KRAS inducible lung cellular models to transform them at will. Combination of ATACseq, ChIPseq and RNAseq allowed us to uncover several conserved super enhancers responsible for transcriptional programs associated to KRAS transformation. We will eliminate them to identify the most critical ones, that in turn will find the most interesting downstream genes, unveiling new therapeutic treatments in lung cancer.

Axis 6: Deciphering the immune tumor microenvironment in lung cancer (project leaders M. Mancini, INSERM staff scientist)

One of the most promising therapeutic strategies in cancer, including lung, arose with the development of immune check point inhibitors since some of the treated patients showed total curation. The caveat is that the percentage of patients that shows these amazing results are very low, i.e., majority of patients have intrinsic resistance, and even more, other patients showing good initial response finally relapse, i.e., develop acquired resistance. In our lab, we have one of the biggest collections of genetic engineered mouse models in Europe to study KRAS-, EGFR-, ALK- and MET-driven lung cancer models, and since all strains are immunocompetent, we are at the moment understanding the contribution of each oncogene to the immune tumor microenvironment.