ALK L1196M

The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors.

ORNi-PCR followed by ddPCR/real-time PCR enables highly sensitive and accurate detection of ALK mutations by liquid biopsy. Although the clinical data are limited, our results show that these methods are potentially useful for identifying ALK-TKI-resistant NSCLC at the early recurrent phase.

Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat...Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM)...At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

V3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.

In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK - TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab and platinum-based chemotherapy could be the alternative treatment option.

Our findings suggest that real-time quantitative monitoring of ALK resistance mutations during the response period could provide a time course of changes while acquiring resistance mutations. This information would be beneficial for designing an appropriate treatment strategy.

In Cohort 1 (n=21), 15 (71%) pts had progressed on alectinib, 5 (24%) on ceritinib and 1 (5%) on ensartinib. In Cohort 2 (n=18), pts had progressed on crizotinib followed by alectinib (n=9, 50%), ceritinib (n=4, 22%) or brigatinib (n=3, 17%); 2 (11%) pts progressed on crizotinib, then ceritinib followed by alectinib...Of 5 pts with ALK resistance mutations (I1171N, V1180L, L1196M, G1202R, and E1210K) who subsequently received lorlatinib, repeat ctDNA NGS after 2 months demonstrated clearance of ALK resistance mutation(s) in 4/5 (80%) pts (i.e. undetectable on repeat testing)... Resistance mechanisms to ALK inhibitors are heterogenous, including both ALK dependent and independent pathways. DDR and cell cycle gene alterations were commonly detected and may represent previously unreported acquired resistance alterations. Comprehensive ctDNA NGS analysis at progression may help detect novel resistance alterations in patients on ALK inhibitors.

The dynamic changes of genomic characteristics during lorlatinib treatment revealed the mutation landscape of Chinese patients with NSCLC after ALK-TKI resistance, indicated that the resistance profile of lorlatinib were heterogeneous, which laid the foundation for subsequent treatment to overcome lorlatinib resistance.

19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations...This was equally effective to the reference drug Repotrectinib (IC = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.