Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Abstract

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma

“…In a phase 2 clinical trial of alectinib for the treatment of R/R ALK+ ALCL(Range, 6-70 years), the ORR after alectinib treatment was 80% and the CR rate was 60%, while the 1-year PFS, event-free survival (EFS), and overall survival (OS) rates were 58.3%, 70.0%, and 70.0% respectively ( 47 ). But a new problem has arisen: Among patients who have a high response to crizotinib monotherapy, about 30-40% of patients have developed further resistance to the drug ( 48 ). ALK mutation/amplification reduces sensitivity to ALK TKIs, necessitating a switch to another drug.…”

“…ALK+ ALCL tumor cells also develop ALK TKI resistance through amplification of NPM–ALK, which was shown to be overexpressed in ALK+ALCL-resistant cell lines ( 48 , 55 , 57 , 58 ).…”

“…The use of ALK TKI combinations can delay the development of ALK resistance. Crizotinib combined with everolimus, CHOP, decitabine, and trametinib prolonged the emergence of resistance, possibly because of a reduction in the dose of individual drugs and the effects of dual targeting ( 48 ).…”

“…Elevated expression of IL-10RA not only confers resistance to crizotinib but also to second- or third-generation inhibitors. Accordingly, ALK TKI combined with IL-10 pathway inhibitors (e.g., STAT3/pan-JAK/TYK2 inhibitors) may be effective ( 48 ) in patients who are resistant to ALK TKIs and have high IL-10RA expression. TYK2 acts upstream of STAT3; it was reported that the survival of ALK+ ALCL cells depended on TYK2/STAT1/MCL1.…”

“…In a multicenter clinical study of cidapenem in R/R PTCL, patients with ALK+ ALCL treated with cidapenem had a higher ORR (66.67%) and disease control rate (83.33%) and better prognosis compared to those with other PTCL subtypes ( 129 ). The use of decitabine (a DNA methyltransferase inhibitor) not only enhanced the efficacy of ALK TKIs but also prolonged the time to emergence of drug resistance by more than 3 fold compared to monotherapy ( 48 ) ( Figure 4B ).…”