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Enhanced antitumor effect of alectinib in combination with cyclin-dependent kinase 4/6 inhibitor against RET-fusion-positive non-small cell lung cancer cells.

ABSTRACT: Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for 1% of lung adenocarcinoma. Although small molecule agents with RET kinase inhibitory activity such as alectinib, vandetanib, and cabozantinib have been clinically evaluated in RET-fusion-positive NSCLC, an effective monotherapy regimen has not been established. We explored agents to use in combination with alectinib to enhance the antitumor effect of alectinib against RET-fusion cells. Cell proliferation under co-treatment with alectinib plus each of six chemotherapeutic agents or six molecularly targeted agents was evaluated in vitro. The combination effect was analyzed by IC₅₀ isobologram and combination index using LC-2/ad and Ba/F3-KIF5B-RET cells. The in vivo combination effect was investigated in a Ba/F3-KIF5B-RET xenograft model. The phosphorylation levels of proteins regulating proliferation were measured by immunoblotting. Palbociclib, a CDK4/6 inhibitor, showed the greatest synergy against LC-2/ad cells in the isobologram analysis and combination index. This synergistic effect was also observed against Ba/F3-KIF5B-RET cells. Another CDK4/6 inhibitor, abemaciclib, also showed a synergistic effect. In vivo, the combination of alectinib plus palbociclib showed a more enhanced antitumor effect than each single agent in a mouse xenograft model with transplanted Ba/F3-KIF5B-RET cells. This combination suppressed the phosphorylation of S6 and Rb more intensely than did either single agent in both LC-2/ad and Ba/F3-KIF5B-RET cell lines, both in vitro and in vivo. Combination therapy with alectinib plus the CDK4/6 inhibitor enhanced the antitumor effect against RET-fusion-positive cells in vitro and in vivo.

SUBMITTER: Fujimura T

PROVIDER: S-EPMC7515507 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.Patients and methodsThis study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.ResultsWe analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.ConclusionsRET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

Project description:OBJECTIVE:To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. STUDY SELECTION AND DATA ABSTRACTION:Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. DATA SYNTHESIS:In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). CONCLUSIONS:Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.

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Enhanced antitumor effect of alectinib in combination with cyclin-dependent kinase 4/6 inhibitor against RET-fusion-positive non-small cell lung cancer cells.

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