Claudia Cardone1, Bernadette Blauensteiner2, Veronica Moreno-Viedma2, Giulia Martini3, Vittorio Simeon4, Pietro P Vitiello3, Davide Ciardiello3, Valentina Belli3, Nunzia Matrone3, Teresa Troiani3, Floriana Morgillo3, Federica Zito Marino5, Monica Dentice6, Annarita Nappi7, Alessandra Boccaccino8, Carlotta Antoniotti8, Chiara Cremolini8, Filippo Pietrantonio9, Gerald W Prager10, Nicola Normanno11, Evaristo Maiello12, Guillem Argiles13, Elena Elez13, Giuseppe Signoriello4, Renato Franco5, Alfredo Falcone8, Josep Tabernero13, Maria Sibilia2, Fortunato Ciardiello3, Erika Martinelli14. 1. Department of Precision Medicine, Università Degli Studi Della Campania "Luigi Vanvitelli", Naples, Italy. Electronic address: cardone.cla@gmail.com. 2. Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Wien, Austria. 3. Department of Precision Medicine, Università Degli Studi Della Campania "Luigi Vanvitelli", Naples, Italy. 4. Department of Public, Clinical and Preventive Medicine, Medical Statistics Unit, Università Degli Studi Della Campania "Luigi Vanvitelli", Naples, Italy. 5. Pathology Unit, Università Degli Studi Della Campania "Luigi Vanvitelli", Naples, Italy. 6. Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. 7. Department of Public Health, University of Naples "Federico II", Naples, Italy. 8. Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy. 9. Fondazione IRCCS Istituto Nazionale Dei Tumori, Università di Milano, Milan, Italy. 10. Department of Medicine I, Division of Oncology, Medical University of Vienna, Wien, Austria. 11. Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy. 12. Department of Oncology and Hematology, Foundation IRCCS 'Casa Sollievo Della Sofferenza', San Giovanni Rotondo, Italy. 13. Vall D'Hebron University Hospital (HUVH) and Vall D'Hebron Institute of Oncology (VHIO), UVic-UCC, IOB-Quiron, Barcelona, Spain. 14. Department of Precision Medicine, Università Degli Studi Della Campania "Luigi Vanvitelli", Naples, Italy. Electronic address: erika.martinelli@unicampania.it.
Abstract
BACKGROUND: RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. METHODS: AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR-based therapy; RAS mutant patients (N = 171) received anti-angiogenic-based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. RESULTS: AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients. CONCLUSIONS: AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.
BACKGROUND: RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. METHODS:AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR-based therapy; RAS mutant patients (N = 171) received anti-angiogenic-based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. RESULTS:AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractorypatients. CONCLUSIONS:AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.
Authors: Mari Iida; Nellie K McDaniel; Kourtney L Kostecki; Noah B Welke; Carlene A Kranjac; Peng Liu; Colin Longhurst; Justine Y Bruce; Seungpyo Hong; Ravi Salgia; Deric L Wheeler Journal: BMC Cancer Date: 2022-04-23 Impact factor: 4.638