1772P - Phosphoproteomic biomarker for afatinib response stratification in advanced chordoma

Background

For advanced chordoma, no standard systemic therapy exists, and the low incidence of targetable genetic alterations limits the impact of genomics in precision oncology efforts. Reports of aberrant receptor tyrosine kinase (RTK) expression or activity in chordoma suggest that these tumors might respond to RTK inhibition, but kinase inhibitors have shown modest clinical activity in patients, possibly because no molecular biomarker exists to identify responder patients.

Methods

We generated phosphoproteome profiles of > 100 chordoma patients and 14 chordoma cell lines and developed a new tumor pathway activity (TUPAC) scoring methodology to infer aberrant RTK activity using > 8,000 proteins and 20,000 phosphorylation sites per patient. We found that chordoma cell lines were either sensitive to the EGFR inhibitor afatinib (EC50 < 50 nM) or resistant (EC50 > 1000 nM), providing an opportunity to test the predictive power of using phosphoproteomic TUPAC scores to predict RTK inhibitor sensitivity.

Results

In (phospho)proteome profiling, Chordoma represents a molecularly heterogeneous group of tumors. We discovered aberrant activity for 15 different RTKs in 43% of chordoma patients, notably and most frequently EGFR and MET. In the cell line panel, afatinib sensitivity corresponded with high scores for EGFR activity in 7/8 sensitive cell lines and 3/6 resistant cell lines. Interestingly, EGFR signaling-positive but resistant cell lines showed high type I IFN signaling, previously associated with adaptive resistance to EGFR inhibition in lung cancer. Using the combination of a high EGFR TUPAC score and a low type I IFN signature, the afatinib response can be correctly predicted in 13/14 cell lines. Applying the same stratification scheme in the patient cohort, we predict afatinib response in 15% of advanced chordoma patients.

Conclusions

Although RTKs are not mutated in chordoma, here we use phosphoproteomics to report the detection of aberrant RTK activation in > 40% of advanced chordoma patients – suggesting RTKs may nonetheless represent attractive therapeutic targets in this rare cancer. These data support the testing of phosphoproteome-based biomarkers for selecting advanced chordoma patients who benefit from afatinib or other RTK inhibitors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Chair of Proteomics and Bioanalytics.

Funding

Chordoma Foundation, EU fund.

Disclosure

C. Heilig: Non-financial interests, Personal, Advisory Board: Boehringer Ingelheim; Financial interests, Personal, Funding, Other, Honoraria: Novartis; Financial interests, Personal, Funding, Other, Honoraria: Roche; Financial interests, Institutional, Research funding: Boehringer Ingelheim. S. Fröhling: Non-financial interests, Personal, Advisory Board: Bayer; Non-financial interests, Personal, Advisory Board: Illumina; Non-financial interests, Personal, Advisory Board: Roche; Financial interests, Personal, Funding, Other, Honoraria, Travel, Accomodations, Expenses: PharmaMar; Financial interests, Personal and Institutional, Funding, Other, Honoraria, Travel, Accomodations, Expenses, Research Funding: Roche; Financial interests, Personal and Institutional, Funding, Other, Honoraria, Travel, Accomodations, Expenses, Research Funding: Lilly; Financial interests, Personal, Funding, Honoraria, Travel, Accomodations, Expenses: Amgen; Financial interests, Institutional, Research Funding: AstraZeneca; Financial interests, Institutional, Research Funding: Pfizer. B. Küster: Financial interests, Personal, Shareholder: OmicScouts; Financial interests, Personal, Shareholder: MSAID; Non-financial interests, Personal, Advisory Board: Covant Therapeutics; Financial interests, Institutional, Research funding: Merck; Financial interests, Institutional, Research funding: Boehringer Ingelheim. All other authors have declared no conflicts of interest.