ALK G1202R

Here, we present a patient diagnosed with high grade metastatic inflammatory myofibroblastic tumor driven by a RANBP2::ALK fusion, who later developed an ALK G1202R resistance mutation in the setting of treatment with crizotinib. The patient remains without evidence of disease now 18 months after discontinuing adjuvant lorlatinib. This case illustrates the importance of serial molecular profiling to guide selection of the optimal ALK inhibitor for the best clinical outcomes.

• A PCR-based mutation prediction system was successfully applied to fourth-generation ALK inhibitors. • Neladalkib showed efficacy against G1202R-positive relapses with minimal evidence of secondary resistance mutations. • Sequential combinations of gilteritinib with either neladalkib or ensartinib may sustain efficacy and delay resistance in I1171N-positive relapses.

Plasma cfDNA analysis using NGS is feasible and offers insights into alectinib resistance mechanisms. Early detection of resistance-associated mutations may guide personalized treatment strategies. Larger prospective studies are needed to validate these findings.

The binding free energy of protein-drug interaction was calculated using MM-PBSA based method. The analysis focused on identifying the skeleton of potential leads that could inhibit both the wild-type and drug-resistant mutant (G1202R) ALK protein.

Brigatinib showed substantial activity in crizotinib-pretreated ALK-positive NSCLC with ALK-dependent mechanisms of resistance. Patients with non-ALK canonical drivers did not respond to brigatinib, suggesting alternative therapeutic approaches in that cohort.

To address the resistance issues caused by ALK mutations, this study used Crizotinib as the lead compound and modified its side chain to design and synthesize a series of compounds containing thiadiazole structures...More importantly, compound B11 overcomes the resistance caused by the ALKG1202R mutation. Ultimately, compound B11, which contains a thiadiazole structure, shows promising activity (ALKL1196M IC50 = 5.57 nM; ALKwt IC50 = 9.19 nM; ALKG1202R IC50 = 15.6 nM).

By using WZH-15-125 as the warhead, we designed an ALK PROTAC molecule WZH-17-002 that can efficiently degrade ALK proteins with half maximal degradation concentration (DC50) values of 25 nM. Furthermore, WZH-17-002 suppresses the emergence of drug resistance and exhibits superior in vivo pharmacological efficacy than lorlatinib in ALK G1202R/L1196M xenograft mouse models. These findings suggest a potential strategy for overcoming resistance to ALK TKI therapies.

P2, N=16, Active, not recruiting, University of Sydney | Recruiting --> Active, not recruiting

Although commercially available ALK inhibitors demonstrate favorable clinical efficacy against most Ceritinib-resistant mutants, they exhibit resistance towards G1202R mutants...In vivo pharmacological experiments demonstrated effective tumor growth inhibition without any significant toxic effects on mouse organs caused by Ld-10 administration. Based on these comprehensive findings from our experimental investigations, it can be concluded that Ld-10 holds promising potential as a novel ALK inhibitor.

Here, we analyzed molecular profiles of 108 alectinib-treated patients (first-line and second-line after crizotinib) with confirmed relapse by targeted sequencing of cancer-related genes. After second-line treatment, the most common mutations in v1 were L1196M (42%) and G1269A (25%), while G1202R was detected in 45% of v3 tumors. These findings emphasize the importance of stratifying resistance mechanisms to guide tailored treatment for ALK-positive NSCLCs.

The modeling simulation revealed that the G1202R mutation exerted little effect on the binding of iruplinalkib. Iruplinalkib showed potency to G1202R because of its unique chemical structure and removal of steric clashes, which might be a promising option for ALK-rearranged NSCLC patients with G1202R resistance mutation.

While first-line crizotinib can regulate phosphorylation, mutations in the ALK gene can lead to resistance against ALK inhibitors (ALKi) such as ceritinib and alectinib. Finally, when ABT-199 was combined with ALKi, we observed a wide range of synergistic effects in the WT and G1202R cell models, while the C1156Y and L1196M models showed limited synergy. In conclusion, our findings indicate that BCL2 targeting with ABT-199, in combination with ALKi, can significantly reduce tumor cell survival in Ba/F3 EML4-ALK cell models.