Understanding the response to EGFR targeting therapy in non-small-cell lung cancer using -omics approach

NSCLC is the leading cause of cancer-related death worldwide. EGFR targeted therapy is used to inhibit the progress of NSCLC, but patients inevitably develop resistance to EGFRTKIs. The work presented in this thesis aimed at better understanding response and resistance mechanisms to EGFR-TKIs in NSCLC and to find novel biomarkers as well as drug targets or combination therapies for NSCLC.

Paper I suggested a group of miRNAs with AAGUGC motif as oncomotif-miRNAs. Through the control of their target tumor suppressors, the oncomotif-miRNAs are part of the oncogenic signaling network that regulates NSCLC’s and other types of cancer’s cell proliferation. Paper II identified that BCL6, FGFR2, and JAK3 were upregulated after EGFR-TKI treatment. Moreover, BCL6 together with EGFR were confirmed to contribute to treatment escape. Dual targeting of BCL6 and EGFR could therefore be a potential combination therapy for treating NSCLC. Paper III reported that CDKN2A loss is associated with EGFR-TKIs sensitivity in EGFRwt NSCLC, and that BCL2L1 (encoding for BCL-xL) overexpression existed before EGFR-TKI treatment in a subset of EGFR-TKI responding cell lines. Additionally, EGFRwt/KRASwt, CDKN2A deleted NSCLC is sensitive to BCL-xL and EGFR dual inhibition, which could be a potential combination therapy for patients with this profile. These findings suggest that CDKN2A deletion can be used as a biomarker to select EGFRwt/KRASwt patients for EGFRTKI-based combination therapy. Paper IV identified the upregulation of AXL and GAS6, EMT, MAPK pathway reactivation, and AXL dependent CDK1 phosphorylation as potential resistance mechanisms of the third-generation EGFR-TKIs.

The work summarized in this thesis add new knowledge to understand the EGFR-TKI response and resistance mechanisms in NSCLC. From our work CDKN2A and oncomotif-miRNA have been identified as interesting candidates that can be investigated for use as biomarkers in NSCLC. Moreover, we propose that BCL6 or BCL-xL inhibitors together with EGFR-TKIs should be further investigated as a combination therapy.

List of scientific papers

I. Zhou Y, Frings O, Branca RM, Boekel J, le Sage C, Fredlund E, Agami R, Orre LM. microRNAs with AAGUGC seed motif constitute an integral part of an oncogenic signaling network. Oncogene. 2017 Feb 9;36(6):731–745.
https://doi.org/10.1038/onc.2016.242

II. Zhou Tran Y, Minozada R, Cao X, Johansson HJ, Mamede Branca RM, Seashore-Ludlow B, Orre LM. Immediate adaptation analysis implicates BCL6 as an EGFR-TKI combination therapy target in NSCLC. Mol Cell Proteomics. 2020 June 1; 19(6):928-943.
https://doi.org/10.1074/mcp.RA120.002036

III. Orre LM, Zhou Tran Y, Minozada R, Seashore-Ludlow B, Östling P, Kallioniemi OP, Lehtiö J. CDKN2A status predicts the response to EGFR targeting therapy in EGFRwt NSCLC. [Manuscript]

IV. Zhou Tran Y, Panizza E, Branca RM, Lehtiö J, Orre LM. Integrative proteomics and phosphoproteomics profiling of NSCLC cell lines to explore osimertinib resistance mechanisms. [Manuscript]