Abstract
Simple SummaryDespite success of targeted therapy, cancer cells very often find a way to survive treatment; this eventually causes a tumor to relapse. In a particular type of lymphoma carrying a specific chromosomal rearrangement named anaplastic large-cell lymphoma (ALCL), selective drugs targeting the cause of the disease can induce spectacular remission of chemotherapy-resistant cancer. However, the lymphoma relapses again in about half of the cases, leaving no therapeutic options. We studied the possibility to combine two simultaneous treatments in order to prevent the relapse, starting from the hypothesis that acquiring resistance to two drugs at the same time is statistically very unlikely. We demonstrate that treating lymphoma cells with drug combinations has superior efficacy in comparison with single drug treatments, both in cell cultures and in mice.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.
Highlights
The emergence of resistance is the major limitation to cancer cures
To investigate the feasibility of preventing drug resistance, anaplastic large-cell lymphoma (ALCL) cells were cultured in the presence of different single and combined drugs
We evaluated the coadministration of crizotinib with non-specific anticancer treatments, such as decitabine or chemotherapy; the latter was represented by a combination of cyclophosphamide, doxorubicin and vincristine (CHO), mimicking a CHOP treatment [25]
Summary
The emergence of resistance is the major limitation to cancer cures. Tumors are characterized by genetic instability that leads to random accumulation of mutations in different subclones, resulting in high clonal heterogeneity. The various subpopulations present at diagnosis respond differently to therapies. In this scenario, some tumor cells have a higher probability to survive and will eventually re-expand after a bottleneck induced by a treatment. Some tumor cells have a higher probability to survive and will eventually re-expand after a bottleneck induced by a treatment In most cases, this makes the monotherapy approach rather ineffective in the long term [1]. We applied a combined (targeted) therapy strategy to ALK+ ALCL, a non-Hodgkin peripheral T-cell lymphoma that depends on the activity of ALK fusion proteins, which support cancer growth by constant activation of JAK/STAT, RAS/MEK/ERK and PI3K/AKT pathways [2,3].
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