Treatment of cancers having driving oncogenic mutations
A technology for non-small cell lung cancer and inhibitors, applied in medical preparations containing active ingredients, organic active ingredients, drug combinations, etc., can solve the problems of targeted driver mutations and limited toxicity
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Embodiment 1
[0280] Example 1. NSCLC PDX model groups demonstrated differential sensitivity to Compound 1 treatment.
[0281] NSCLC PDX models (n=60) were treated orally with vehicle or compound 1 (100 mg / kg) daily for up to 28 days. Tumor growth inhibition (TGI) was calculated when tumors reached a prespecified tumor burden or at day 28. Genetic alterations from pretreated samples were assessed using FoundationOne. A TGI of 58% was used as the responder / non-responder cutoff for correlation analyses. like figure 1 As shown, there is a range of efficacy associated with Compound 1 in the cohort of NSCLC PDX models. Certain genetic changes, such as KRAS and EGFR, showed greater sensitivity, while others, such as RB1, showed resistance. The median TGI was 73% for adenocarcinoma and 66% for squamous cell carcinoma.
Embodiment 2
[0282] Example 2. Compound 1 enhances the antiproliferative effect of inhibitors targeting specific oncogenic drivers in vitro
[0283] Lung cancer cell lines (n=40) carrying known oncogenic mutations were screened for their sensitivity to Compound 1 alone or in combination with relevant targeted kinase inhibitors (Crown Bioscience, Taicang, China). like figure 2 As shown, the absolute IC of compound 1 monotherapy 50 Values were calculated using a 2x doubling time cell proliferation assay (minimum 3 days) and used to guide the design of combination treatment experiments. Using the Loewe Additivity model, growth inhibitor values were calculated for compound 1 in combination with dabrafenib, selumetinib, uritinib, dactolisib, osimertinib, crizotinib, alectinib, or lapatinib synergy score. For drug co-screening in NSCLC cell lines, a nominally single-drug IC 50 A 9x9 combinatorial matrix centered on values, measuring cell proliferation for each condition after two popula...
Embodiment 3
[0285] Example 3. Combination therapy with compound 1 enhances antiproliferative and apoptotic signaling pathways
[0286] A549 (KRAS G12S and CDKN2A null) NSCLC cells were treated with compound 1 (0.5 μM), selumetinib (1 μM) and / or uritinib (1 μM) for 48 h. Additionally, H3122 (EML4-ALK fusion) NSCLC cells were treated with compound 1 (0.5 μM) and / or crizotinib (1 μM) for 48 hours. All cells were immunoblotted with α-tubulin as a loading control. like Figure 4A and 4B The enhanced efficacy of the treatment combination with Compound 1 when compared to either monotherapy may be due to the marked inhibition of RB phosphorylation as well as the enhancement of the pro-apoptotic phenotype, as shown in the immunoblot in .
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