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Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer. We identified Polo-like kinase 1 (PLK1), a mitotic kinase, as a resistance mediator whose genomic as well as pharmacological inhibition restored drug sensitivity. Both acquired and de novo resistant models exhibited synergistic growth inhibition upon combination of T-DM1 with a selective PLK1 inhibitor, volasertib, at a wide concentration range of the two drugs. Mechanistically, T-DM1 sensitization upon PLK1 inhibition with volasertib was initiated by a spindle assembly checkpoint (SAC)-dependent mitotic arrest, leading to caspase activation, followed by DNA damage through CDK1-dependent phosphorylation and inactivation of Bcl-2/xL. Furthermore, we showed that Ser70 phosphorylation of Bcl-2 directly regulates apoptosis by disrupting the binding to and sequestration of the pro-apoptotic protein Bim. Importantly, T-DM1 resistance signature or PLK1 expression correlated with cell cycle progression and DNA repair, and predicted a lower sensitivity to taxane/trastuzumab combination in HER2-positive breast cancer patients. Finally, volasertib in combination with T-DM1 greatly synergized in models of T-DM1 resistance in terms of growth inhibition both in three dimensional (3D) cell culture and in vivo. Altogether, our results provide promising pre-clinical evidence for potential testing of T-DM1/volasertib combination in T-DM1 refractory HER2-positive breast cancer patients for whom there is currently no treatment available.

In an optical fibre, we investigate the propagation properties of nonlinear periodic waves (PW) for a generalized mixed nonlinear Schrödinger (GMNLS) equation. The Jacobi elliptic (JE) solutions will be used to find the nonlinear chirp. The chirp varies with two intensity-dependent chirping terms are included in the linear section of the pulse chirp. The presence of the newly discovered periodic waves will be discussed in terms of fibre parameter conditions. The long-wave limit generates a wide range of solitary pulse forms, including topological, non topological, dark, kink, hyperbolic and periodic solitary waves (SW). Our findings show that for periodic and solitary waves, a nonlinear chirp obtains. Finally, under finite perturbations, the stability of these nonlinearly chirped solutions will be quantitatively investigated. • The longitudinal wave dynamical model of nonlinear physics. • Nonlinear analysis and rational solitons and generalized breathers. • The analytical modified methods are applied. [ABSTRACT FROM AUTHOR]