Study and detection of genetic alterations associated with acquired resistance to Anti-EGFR therapy in circulating tumor DNA of patients with colorectal and lung cancer

• Grant number: 15/16854-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): July 01, 2016
• Effective date (End): August 17, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Anamaria Aranha Camargo
• Grantee: Franciele Hinterholz Knebel
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
• Associated scholarship(s): 18/23531-5 - The use of liquid biopsies based on ctDNA sequencing for the detection of residual disease in locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy (nCRT), BE.EP.PD

Abstract

The Epidermal Growth Factor Receptor (EGFR) was the first receptor to be proposed as a target for cancer therapy after two decades of intense research. Anti-EGFR therapies are used in the clinic to treat different types of cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CCR). The tyrosine kinase inhibitors - Gefitinib and Erlotinib - are used to treat NSCLC, and the monoclonal antibodies - Cetuximab and Panitumumab - are used to treat CCR. Treatment response to these drugs depends on the presence of activating mutations in EGFR (L858R and exon 19 deletions) in NSCLC and on the absence of mutations in the KRAS, BRAF and NRAS in CCR. Although these drugs present satisfactory response rates and gains in progression free survival, patients treated with these drugs invariably develop resistance to treatment (acquired resistance), leading to disease progression and death. Genetic heterogeneity, intrinsic to human tumors, and selection of genetic alterations that confer resistance to targeted therapy has been recognized as crucial for the development of acquired resistance to anti-EGFR drugs. Besides the occurence of mutations in the region corresponding to the ectodomain of EGFR (T790M) and MET gene amplification, which are often found in patients with NSCLC, mutations in genes members of the EGFR pathway, such as KRAS, BRAF and NRAS, have also been reported in CCR patients with acquired resistance to anti-EGFR therapy. However, the presence of these somatic genetic alterations can explain only a fraction of the acquired resistance cases. Other mechanisms exist and need to be characterized. In this project, we intend to monitor the emergence of genetic alterations known to be associated with acquired resistance to anti-EGFR therapy in circulating tumor DNA (ctDNA) obtained from liquid biopsies collected from NSCLC patients treated with Gefitinib and Erlotinib and CCR patients treated with panitumumab and Cetuximab. We also intend to characterize new genetic alterations associated with acquired resistance to anti-EGFR therapy through direct sequencing of ctDNA from patients with NSCLC and CCR experiencing disease progression during anti-EGFR therapy. Our aim is to develop and validate molecular tools to study and detect acquired resistance to anti-EGFR therapy in patients with colon cancer and lung. Early detection and additional charcaterization of the molecular mechanisms related to acquired resistance to anti-EGFR therapy may have important implications in disease outcome by avoiding inefective, toxic and expensive treatment and by allowing, in some cases, the use of more effective second line therapies to slow disease progression. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

KNEBEL, FRANCIELE H.; BARBER, LOUISE J.; NEWEY, ALICE; KLEFTOGIANNIS, DIMITRIOS; WOOLSTON, ANDREW; GRIFFITHS, BEATRICE; FENWICK, KERRY; BETTONI, FABIANA; SILVA ALMEIDA RIBEIRO, MAURICIO FERNANDO; FONSECA, LEONARDO; et al. Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy. CANCERS, v. 12, n. 12, DEC 2020. (15/16854-4, 18/23531-5)

KNEBEL, FRANCIELE H.; BETTONI, FABIANA; DA FONSECA, LEONARDO G.; CAMARGO, ANAMARIA A.; SABBAGA, JORGE; JARDIM, DENIS L.. Circulating Tumor DNA Detection in the Management of Anti-EGFR Therapy for Advanced Colorectal Cancer. FRONTIERS IN ONCOLOGY, v. 9, MAR 22 2019. (15/16854-4)