Lung cancer kills about a million people every year worldwide, and it is estimated that during the 21st century over 250 million people will die from this aggressive disease. Around 40% of all lung cancer belongs to lung adenocarcinoma. The three most important oncogenes altered in human lung adenocarcinoma are KRAS, EGFR, and EML4/ALK, accounting from more than 50% of patients in western countries to almost 80% of patients in some Asian countries as Korea.
We have previously demonstrated that inhibition of the Notch pathway by using a g-secretase inhibitor (GSI) totally arrest tumor growth in KRAS-driven lung adenocarcinoma in vivo, what is really challenging today in the clinic since there is no targeted therapy for this type of mutation. In an effort to expand this finding to other oncogenic insults important in human lung adenocarcinoma, in the last years we have obtained mouse models to study lung adenocarcinoma-driven by several other oncogenes as EGFR, EML4/ALK and c-MET.
As an example of the work developed in the laboratory, the figure below represents sections of lungs with tumors from EGFRT790M/L858R mice. We are showing that tumor burden present in non treated lung is partially decreased upon treatment with the g-secretase DBZ (notch inhibitor), unchanged by gefitinib treatment as expected since EGFRT790M confers resistance to this TKI. Importantly, when combined both drugs there is a strong inhibition of tumor growth promoted by the re-sensitization of these tumors to gefitinib. We have also shown that Notch inhibition can re-sensitize EGFR-driven lung adenocarcinoma with EGFRC797S mutations to osimertinib. These data offer a new therapeutic opportunity to EGFR mutated patients that after relapse to osimertinib treatment do not have other therapeutic possibility than conventional chemotherapy.
Our interest expands to EML4/ALK and c-MET oncogenic drivers and we are currently trying to understand how these oncogenic insults develop resistance in vivo to dedicated TKIs as alectinib and merestinib respectively. Even more, we are also extending the benefit of Notch inhibition to the first line treatment for KRAS-driven lung adenocarcinoma patients, i.e. platin-based therapy, that is also the last option for EML4/ALK or EGFR patients that relapse to last generations of TKIs.
Our major goal is to develop new treatments in LUAD and translate them into the clinic as fast as possible by performing Phase 1 innovative trials at ICM. To illustrate our interest, we are at the moment starting the procedure to implement a clinical trial at ICM combining osimertinib and Notch inhibitors.
Our results are very encouraging but still we have plenty of open questions :
1) Can we target the Notch pathway in a more rational way, i.e., affecting at minimum the non-tumoral cells?
2) Can we avoid the generation of resistance to targeted therapy?
3) What is the contribution of the stroma in resistance development and/or in Notch pathway activation in the cancer cells?
4) What are the mechanisms for the resistance to Notch inhibition in lung adenocarcinoma?
5) Can we target the MET-induced resistance to osimertinib in EGFR-driven lung adenocarcinoma?
6) What is the crosstalk between epigenetics and the Notch pathway in lung adenocarcinoma? These are some of the questions we would like to address in the coming years in our laboratory.