Resistance to ALK inhibitors

Universita Degli Studi Milano Bicocca

Prof. Carlo Gambacorti-Passerini


Publication Link ORCID Link

Clinical research into disease mechanisms of neoplastic disease

Research Interest

Prof. Carlo Gambacorti-Passerini is a leading physician in the field of oncogenic fusion proteins and tyrosine kinase inhibitors. He has contributed significantly to the development of imatinib for the treatment of CML and successfully pioneered an ALK+ lymphoma patient therapy with ALK inhibitors. His research centers on identifying the molecular pathogenesis of hematological cancers using genome sequencing. He is interested in molecular mechanisms governing the transition from chronic phase to blast crisis in CML. In addition he is engaged in target validation of oncogenic fusion genes, structural characterization and screening of small-molecule inhibitors and new tyrosine kinase inhibitors to overcome therapy resistance in patients with ALK+ lymphomas.

Geeta Sharma

Research student



Research Interest

I was born in a small town of Haryana in India. I received my Bachelor’s degree in Biotechnology from Amity University, India. To explore and gain more insight into the research field, I enrolled into the master’s program of University College Dublin, Ireland. Amongst the various topics I came across, ‘Targeted Therapies for Cancer treatment’ interested me the most. I wrote my master’s thesis on the topic “Immunohistochemical validation of biomarkers associated with poor prognosis in Invasive Lobular Carcinoma (ILC)”.

Within the ALKATRAS training network, I will be working on the project “Resistance to ALK inhibitors” in Prof Carlo Gambacorti-Passerini’s laboratory. The main goal of my project is to understand and find out about the mutations which confer resistance against ALK inhibitors (crizotinib and lorlatinib) in ALK positive Anaplastic Large Cell Lymphoma (ALCL) patients . In long-term, these findings will help in improving the prognosis of the cancer patients.

Research description

Although Crizotinib treatment of advanced ALK+ ALCL yields high response rates, in advanced chemoresistant ALK+ lymphoma patients, approximately half of the patients relapse within 3-4 months. We hypothesize that the molecular anatomy of the tumours at diagnosis (number and types of genetic alterations) dictates their long-term prognosis.

Our goal is to: Perform WES of primary FFPE biopsy specimens of patients treated with Crizotinib to determine mutations, in/dels and copy number variations; determine mutations in the two patient groups (relapse/no relapse), which might confer drug resistance; predict signal transduction pathways that are affected by the identified mutations.

Expected Results:
Characterization of genetic determinants of response vs non-response to Crizotinib; identification of resistance mechanisms in relapsed ALCL patients and cell lines; analysis of synergism with other drugs.

Planned secondment(s):
Year 1: Galkem (PO#4) – Development and assessment of ALK inhibitors – 1 month;
Year 2:University of Cambridge (B#1) – assessment of murine xenograft/transgenic models of ALCL for their response to novel inhibitors -1 month

Latest publication: