High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.

Kinetic resolution of (R,S)-2-butanol using enzymatic synthesis of esters.

Kinetic resolution of (R,S)-2-butanol using enzymatic synthesis of esters has been studied. (R,S)-2-Butanol is commonly found as a racemic mixture, and the products of its esterification are racemic mixtures too. This work is of great significance in the field of the enzymatic kinetic resolution due to the little information found in literature about the resolution of (R,S)-2-butanol as pure compound. So, this article is a contribution about the enzymatic resolution of (R,S)-2-butanol. The reaction here studied is the esterification/transesterification of (R,S)-2-butanol in organic media (n-hexane) using as biocatalyst the lipase Novozym 435®. The main target of this study is to analyze the influence of certain variables in this reaction. Some of these variables are acyl donor (acids and esters), concentration of substrates, enzyme/substrate ratio, and temperature. The main conclusions of this study are the positive effect of higher substrates concentration (1.5 M) and larger amount of enzyme (13.8 g mol(-1) substrate) on kinetic resolution rate but not a very noticeable effect on enantiomeric excesses. The longer the carboxylic acid chain is, the better results are obtained. Besides to achieve a satisfactory kinetic resolution, it is recommendable to select reaction times (180 min) at which the highest substrate enantiomeric excess is reached (~60%). The temperature has not an appreciable influence on the resolution in the range studied (40-60 °C). When an ester (vinyl acetate) is used as acyl donor, the resolution shows better results than when using a carboxylic acid as acyl donor (ee(s) ~90% at 90 min). Moreover, Michaelis-Menten parameters, v(max) and K(M), were determined, 0.04 mol l(-1) min(-1) and 0.41 mol l(-1), respectively.

Adsorption and diffusion parameters of methane and nitrogen on microwave-synthesized ETS-4.

ETS-4 is a titanium silicate developed by Engelhard Corporation, which possesses a small pore network, the size of which can be reduced by heat treatment to improve its kinetic selectivity in nitrogen/methane separation. Most of the reported studies about ETS-4 employ crystals synthesized with conventional heating. Furthermore, information available on the adsorption properties of ETS-4, especially the diffusion properties, is scarce. In this work, Na-ETS-4 crystals have been synthesized by microwave heating and have been exchanged with strontium to obtain Sr-ETS-4 using also microwave heating. This method for obtaining the strontium form of ETS-4 has not been reported before. Both materials have been dehydrated to reduce their pore size. The adsorption and diffusion parameters of nitrogen and methane on these materials, which have not been measured for microwave-synthesized ETS-4 up to the present date, have been estimated by modeling the desorption breakthrough curves of both gases using a fixed bed of ETS-4 crystals. The kinetic selectivity of nitrogen over methane at 298 K of microwave-synthesized Sr-ETS-4 is 26. This value is higher than the maxima reported in the literature for this material.