Martin Sos - A 11

Despite major improvements in targeted therapies in the last years, lung cancer still remains one of the deadliest cancers worldwide. Targeted drugs that inhibit mutant EGFR in lung adenocarcinoma has dramatically prolonged the overall survival of these patients. However, the development of resistance remains inevitable. In this project, we aim for understanding the molecular drivers that shape the evolutionary process of resistance in EGFR-mutant lung tumors.

Lung cancer is the leading cause of cancer death in men and women in developed countries. Over the last decade novel techniques like next-generation sequencing and high-throughput analyses have enabled us and other groups to systematically classify lung tumors on a genomic level and to develop novel, targeted therapies for genetically defined subgroups of lung cancer patients. This type of a precision medicine approach is based on the observation that mutant oncogenes such as mutant EGFR or rearranged RET can drive growth of individual tumors and may serve as Achilles heels for an effective therapy. 

However, the targeted treatment of oncogenically driven tumors inevitably leads to the selection of resistant clones and the recurrence of disease. This is not too surprising considering the genomic complexity of cancer and the dynamic evolution of unique cell clones that contribute to the heterogeneity of individual tumors. In our project, we aimed at characterizing the genomic and molecular dynamics of clonal evolution in EGFR-driven lung tumors and their implication for therapeutic responses to targeted drugs. For this purpose, we combined systematic in vitro modelling of tumor resistance development and the analysis of patient cohorts with several complementary genomic and transcriptomic approaches. 

Furthermore, we embarked on the characterization of therapeutic response to RET targeted agents in RET rearranged lung cancer models. Here, we were able to identify structural elements that are responsible for drug efficacy but also molecular drivers that limit the overall response to targeted agents (Plenker et al., Science Transl Med 2017). 

This approach provides important insights into the molecular processes that drive resistance to targeted inhibition of oncogenic signalling and may help to further improve the treatment options for lung cancer patients.

During our work with patient samples from a study investigating the effectiveness of third-generation EGFR inhibitors, we have shown the potential to elucidate the diversity of occurring resistance patterns (Ortiz-Cuaran et al., 2016).

Within this project part, we systematically extend this approach to samples obtained before and after treatment with different EGFR inhibitors. 

One of the currently investigated routes is the characterization of a novel resistance mutation within EGFR that arises as a subclone in EGFR TKI treated patients (Fig. 2). This novel mechanism shifts the sensitivity from the class of third-generation EGFR inhibitors to second-generation EGFR inhibitors (Fassunke et al., Nat Comm 2018). This data is closely related to our results obtained in RET-driven tumors in which we identified novel determinants of drug resistance (Plenker et al., Science Trans Med 2017).

Aim 2: Functionally linking the subclonal evolution of EGFR-driven lung tumors with their vulnerability to targeted drugs

Perspectives 

1. Fassunke J, Müller F, Keul M, Michels S, Dammert MA, Schmitt A, Plenker D, Lategahn J, Heydt C, Brägelmann J, Tumbrink HL, Alber Y, Klein S, Heimsoeth A, Dahmen I, Fischer RN, Scheffler M, Ihle MA, Priesner V, Scheel AH, Wagener S, Kron A, Frank K, Garbert K, Persigehl T, Püsken M, Haneder S, Schaaf B, Rodermann E, Engel-Riedel W, Felip E, Smit EF, Merkelbach-Bruse S, Reinhardt HC, Kast SM, Wolf J, Rauh D, Büttner R, Sos ML (2018). Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun. 9(1), 4655.

2. Plenker D, Riedel M, Brägelmann J, Dammert MA, Chauhan R, Knowles PP, Lorenz C, Keul M, Bührmann M, Pagel O, Tischler V, Scheel AH, Schütte D, Song Y, Stark J, Mrugalla F, Alber Y, Richters A, Engel J, Leenders F, Heuckmann JM, Wolf J, Diebold J, Pall G, Peifer M, Aerts M, Gevaert K, Zahedi RP, Buettner R, Shokat KM, McDonald NQ, Kast SM, Gautschi O, Thomas RK, Sos ML (2017). Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med. 9(394).

3. Ortiz-Cuaran S, Scheffler M, Plenker D, Dahmen L, Scheel AH, Fernandez-Cuesta  L, Meder L, Lovly CM, Persigehl T, Merkelbach-Bruse S, Bos M, Michels S, Fischer  R, Albus K, König K, Schildhaus HU, Fassunke J, Ihle MA, Pasternack H, Heydt C, Becker C, Altmüller J, Ji H, Müller C, Florin A, Heuckmann JM, Nuernberg P, Ansén S, Heukamp LC, Berg J, Pao W, Peifer M, Buettner R, Wolf J, Thomas RK, Sos ML (2016). Heterogeneous Mechanisms of Primary and Acquired Resistance to Third Generation EGFR Inhibitors. Clin Cancer Res. 22(19), 4837-4847.