STRN-ALK rearranged pediatric malignant peritoneal mesothelioma – Functional testing of 527 cancer drugs in patient-derived cancer cells

Abstract

Highlights First study to establish in real-time STRN-ALK fusion positive pediatric patient-derived cancer cells (PDCs). Ex vivo sensitivity testing of PDCs to 527 oncology drugs was analysed by high-throughput drug testing. Comparison of efficacies of eight ALK inhibitors towards PDCs both in 2D and 3D. Drug combination synergies identified between ALK and MEK and ALK and PI3K/mTOR inhibitors. Our precision medicine platform supported successful clinical use of crizotinib in patient treatment.

STRN-ALK Fusion in a Case of Malignant Peritoneal Mesothelioma: Mixed Response to Crizotinib, Mode of Resistance, and Brigatinib Sequential Therapy

“…12 In a third recent case report, crizotinib combined with cisplatin and gemcitabine was used to treat a 5-year-old chemotherapy-refractory pediatric patient, who achieved a complete remission lasting for at least 3 years. 14 A drug screening approach of primary MPM-patient-derived cancer cells revealed their sensitivity to various ALK, MEK, and ERK inhibitors and the synergistic antigrowth effect of combining ALK inhibitors with MEK and PI3K/ mTOR inhibitors. 14 In the case reported here, the effect of crizotinib treatment lasted for about 3 months until a mixed response in the different tumor sites and a new pelvic tumor manifestation and hepatic metastases occurred.…”

“…14 A drug screening approach of primary MPM-patient-derived cancer cells revealed their sensitivity to various ALK, MEK, and ERK inhibitors and the synergistic antigrowth effect of combining ALK inhibitors with MEK and PI3K/ mTOR inhibitors. 14 In the case reported here, the effect of crizotinib treatment lasted for about 3 months until a mixed response in the different tumor sites and a new pelvic tumor manifestation and hepatic metastases occurred. Notably, to our knowledge, this is the first time an ensuing resistance mutation (p. L1196M ALK) has been detected and functionally characterized in MPM and subsequently treated with brigatinib.…”

“…Subsequently, three more cases of STRN-ALK rearrangements in MPM have been published individually. 6,13,14 In non-small-cell lung cancer (NSCLC), the discovery of specific drugs targeting ALK rearrangements led to significant therapeutic advances. Currently, various ALK inhibitors, namely, ceritinib, crizotinib, and alectinib, are used as first-line treatment in adult ALKpositive advanced NSCLC.…”

Mesothelioma with ALK gene mutations in two pediatric patients: Clinical course and outcome

“…6 Treatment with ALK inhibitors demonstrated objective response in tumor burden. 7,[13][14][15][16] Nonresponse was noted in an adult patient whose tumor had ALK mutation with absent fusion partner. Drug sensitivity assay on cell culture showed highest response to brigatinib, lowest response to certinib.…”

“…Drug sensitivity assay on cell culture showed highest response to brigatinib, lowest response to certinib. [13][14][15] Synergism with MEK (cobetinib) and mTOR/PI3K (gedatolisib) inhibitors was efficient for certinib. 14,16 Crizotinib with chemotherapy was given in an 8-year-old female in remission for 3 years.…”