Lorlatinib and Bevacizumab Activity in ALK-Rearranged Lung Cancers After Lorlatinib Progression.
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ABSTRACT:
SUBMITTER: Choudhury NJ
PROVIDER: S-EPMC7713518 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Lorlatinib and Bevacizumab Activity in <i>ALK-</i>Rearranged Lung Cancers After Lorlatinib Progression.
Choudhury Noura J NJ Young Robert J RJ Sellitti Matthew M Miller Alexandra A Drilon Alexander A
JCO precision oncology 20201102
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Project description:PurposeLorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental designResistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.ResultsDiverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial-mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.ConclusionsThis study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.
| S-EPMC6942925 | biostudies-literature
Project description:Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.
| S-EPMC9879975 | biostudies-literature
Project description:ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.
| S-EPMC7904790 | biostudies-literature
Project description:Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.
| S-EPMC3385512 | biostudies-literature
Project description:Anaplastic lymphoma kinase (ALK) fusion is found in ~3%-5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance.
| S-EPMC8931094 | biostudies-literature
Project description:Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK-rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in ALK-rearranged lung cancer cells in vitro. We established two different lorlatinib-resistant ALK-rearranged lung cancer cell lines (H3122LR and A925LLR) via long-term administration of lorlatinib. These resistant cells did not harbor the secondary ALK mutations and showed cross-resistance to the other kinds of ALK-TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan-HER inhibitors or genetic knockdown of HER3 with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1/HER3 activation. These findings demonstrated that targeting NRG1/HER3 is a potential novel therapeutic option for lorlatinib-resistant ALK-rearranged lung cancer.
| S-EPMC9807501 | biostudies-literature
Project description:IntroductionOver the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival.MethodsMulticenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis.ResultsThe population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2-4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01).ConclusionsLorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.
| S-EPMC10106481 | biostudies-literature
Project description:The identification of oncogenic alterations in subsets of patients with non-small cell lung cancer (NSCLC) is transforming clinical care. Genomic rearrangements in anaplastic lymphoma kinase (ALK) are detected in 3% to 7% of patients with NSCLC. The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and was recently approved by the U.S. Food and Drug Administration. Crizotinib is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, new challenges in the diagnosis and treatment of this subset of NSCLC have emerged, including the need to determine the most effective means of diagnosing ALK-rearranged NSCLC and the emergence of acquired drug resistance to crizotinib. In this review, we discuss current strategies for treatment and diagnosis, as well as the current knowledge about mechanisms of acquired resistance to crizotinib. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.
| S-EPMC3477548 | biostudies-literature
Project description:Objective: Oncogenic echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion proteins found in non-small cell lung cancers (NSCLC) are constitutively phosphorylated and activated by dimerization via the coiled-coil domain (cc) within EML4. Here, we investigated whether disruption of ALK fusion protein oligomerization via competitive cc mimetic compounds could be a therapeutic strategy for EML4-ALK NSCLC. Methods: A Ba/F3 cell model was created that expressed an ALK intracellular domain in which the dimer/monomer state is ligand-regulated. This novel cell model was used to investigate the effect of disrupting ALK fusion protein oligomerization on tumor cell growth in vitro and in vivo using nude mice. Subsequently, the antiproliferative effects of endogenous cc domain co-expression and mimetic cc peptides were assayed in EML4-ALK cancer cell lines. Results: Cells induced to express monomeric ALK in vitro did not survive. When transplanted into mice, induction of monomers abrogated tumor formation. Using a fluorescent protein system to quantify protein-protein interactions of EML4-ALK and EML4cc, we demonstrated that co-expression of EML4cc suppressed EML4-ALK assembly concomitant with decreasing the rate of tumor growth in vitro and in vivo. In EML4-ALK cancer cell lines, administration of synthetic EML4cc peptide elicited a decrease of phosphorylation of ALK leading to reduction in tumor cell growth. Conclusions: Our findings support the monomerization of ALK fusion proteins using EML4cc peptides for competitive inhibition of dimerization as a promising therapeutic strategy for EML4-ALK NSCLC. Further studies are warranted to explore the use of specific cc peptide as a therapeutic option for other lung cancers harboring driver fusion genes containing a cc or oligomerization domain within the fusion partner.
| S-EPMC7142238 | biostudies-literature
Project description:Second and third-generation ALK-TKI inhibitors have showed better activity and have replaced crizotinib in most of cases of advanced ALK-rearranged lung adenocarcinoma. The emergence of resistance adversely affects also the activity of these newer drugs; in particular, lorlatinib often shows multiple and complex resistance mechanisms. The case reported here highlights the importance of reassessing the biomolecular profile during the disease course, both by tissutal and liquid biopsy, with the aim of improving the knowledge of these resistance mechanisms, and so identifying new drugs or sequences able to optimize the management of these patients.
| S-EPMC8947659 | biostudies-literature