Two novel strategies to overcome the resistance to ALK tyrosine kinase inhibitor drugs: Macrocyclic inhibitors and proteolysis-targeting chimeras

Lung cancer is the most malignant tumor in the worldwide. About 3%-5% non-small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK-targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one-third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis-targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib-resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed. READ ARTICLE

MedComm DOI: 10.1002/mco2.42

Authors: Song X, Zhong H, Qu X, Yang L and Jiang B.

SPACEWALK: Plasma NGS for remote evaluation of ALK drug resistance in advanced NSCLC

Introduction: Precision therapy for cancer drug resistance requires detection of resistance mutations and treatment with appropriate targeted therapies. This paradigm is well established in EGFR-mutant NSCLC, yet our understanding of drug resistance in ALK-positive NSCLC is limited. Next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) now permits noninvasive interrogation of drug resistance. To facilitate improved understanding of ALK drug resistance and the effectiveness of treatment strategies, we launched this remote participation study. Conclusions: Plasma NGS permits the detection of targetable resistance mechanisms in patients with ALK-positive NSCLC and drug resistance. Sensitivity of different plasma NGS assays for ALK fusions varies. This assay may help guide oncologists across the country to select best treatment options after resistance. Such remote-participation studies may offer a new mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1557-3265.LiqBiop20-A28

Authors: Marissa N. Lawrence, Rubii M. Tamen, Alicia Sable-Hunt, Seyed Ali Hosseini, George R. Simon, Jonathan W. Riess, Geoffrey R. Oxnard.

Conference PaperKirk SmithJanuary 16, 2020NGS, resistance mechanisms, ALK, drug resistance

Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

Lorlatinib 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. Resistance 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. This study shows that..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1104

Authors: Recondo G, Mezquita L, Facchinetti F, Planchard D, Gazzah A, Bigot L, Rizvi AZ, Frias RL, Thiery JP, Scoazec JY, Sourisseau T, Howarth K, Deas O, Samofalova D, Galissant J, Tesson P, Braye F, Naltet C, Lavaud P, Mahjoubi L, Abou Lovergne A, Vassal G, Bahleda R, Hollebecque A, Nicotra C, Ngo-Camus M, Michiels S, Lacroix L, Richon C, Auger N, De Baere T, Tselikas L, Solary E, Angevin E, Eggermont AM, Andre F, Massard C, Olaussen KA, Soria JC, Besse B, Friboulet L.

Pre-ClinicalKirk SmithJanuary 1, 2020Lorlatinib, resistance mechanisms

Abstract A125: Predication of lorlatinib resistance mechanisms and therapeutic strategies to overcome the resistance in ALK rearranged non-small cell lung cancer

Introduction: ALK fusion gene is found in 3-5% of NSCLC patients. As the resultant ALK fusion protein constitutively activates ALK tyrosine kinase that causes tumorigenesis, ALK tyrosine kinase inhibitors have been developed for the treatment of ALK rearranged cancer and currently five ALK-TKIs have been clinically applied. Now, alectinib is widely used in first-line therapy. However, most of the patients experience the emergence of alectinib resistance due to the secondary mutation in ALK kinase domain such as I1171N or G1202R. Lorlatinib, third generation ALK-TKI, has shown to be able to overcome any of the earlier generation ALK-TKI resistant single point mutants including G1202R and I1171N. Conclusion: Our results imply that the clinical sequences after lorlatinib resistance using biopsy or liquid-biopsy might provide important information to choose the effective sequential ALK-TKI therapy. Further studies are still needed to uncover the unidentified lorlatinib resistance mechanisms. READ ARTICLE

Molecular Targets and Cancer Therapeutics DOI:10.1158/1535-7163.TARG-19-A125

Authors: Koutaroh Okada, Mitsugu Araki, Tomoko Oh-hara, Makoto Nishio, Yasushi Okuno, Naoya Fujita and Ryohei Katayama