KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.

The condensation of malonoaldehyde derivatives with either a 3-amino-[1,2,4]-triazole or a 3,5-diamino-[1,2,4]-triazole precursor was studied. In agreement with previous reports, two different bicycles, namely, bearing the regioisomeric [1,2,4]triazolo[1,5-a]pyrimidine (1) or [1,2,4]triazolo[4,3-a]pyrimidine (2) structural surrogates, could be obtained. We found that, depending on the triazole precursor, only one regioisomer resulted, either of the 1 or 2 series. We also observed that these two structural surrogates could be unambiguously differentiated by indirectly measuring their (15)N chemical shifts by (1)H-(15)N HMBC experiments. The occasional conversion of [1,2,4]triazolo[4,3-a]pyrimidines to the [1,2,4]triazolo[1,5-a]pyrimidine counterparts could be unequivocally determined by (15)N NMR data.

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