We conclude that dasatinib with cisplatin is a rational drug combination for testing in triple-negative breast cancer.

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Our results suggest that HER-2-non-amplified breast cancer cells, with low but detectable levels of HER-2 protein, can bind trastuzumab and initiate ADCC.

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies.

An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management.

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8 Abstract Approximately 20 % of human breast cancers 9 (BC) overexpress HER2 protein, and HER2-positivity is 10 associated with a worse prognosis. Although HER2-tar-11 geted therapies have significantly improved outcomes for 12 HER2-positive BC patients, resistance to trastuzumab-13 based therapy remains a clinical problem. In order to better 14 understand resistance to HER2-targeted therapies in HER2-15 positive BC, it is necessary to examine HER family sig-16 nalling as a whole. An extensive literature search was 17 carried out to critically assess the current knowledge of 18 HER family signalling in HER2-positive BC and response 19 to HER2-targeted therapy. Known mechanisms of trast-20 uzumab resistance include reduced receptor-antibody 21 binding (MUC4, p95HER2), increased signalling through 22 alternative HER family receptor tyrosine kinases 23 (RTK), altered intracellular signalling involving loss of 24 PTEN, reduced p27kip1, or increased PI3 K/AKT activity 25 and altered signalling via non-HER family RTKs such as 26 IGF1R. Emerging strategies to circumvent resistance to 27 HER2-targeted therapies in HER2-positive BC include co-28 targeting HER2/PI3 K, pan-HER family inhibition, and 29 novel therapies such as T-DM1. There is evidence that 30 immunity plays a key role in the efficacy of HER-targeted 31 therapy, and efforts are being made to exploit the immune 32 system in order to improve the efficacy of current anti-HER 33 therapies. With our rapidly expanding understanding of 34 HER2 signalling mechanisms along with the repertoire of 35 HER family and other targeted therapies, it is likely that the 36 near future holds further dramatic improvements to the 37 prognosis of women with HER2-positive BC. 38 39 Keywords Trastuzumab · HER2 · Breast cancer · 40 PI3 K 41 Introduction 42 BC is the second most common cancer in the world, and the 43 fifth highest cause of cancer mortality worldwide [1]. 20 % of 44 human BC's overexpress HER2, and HER2-positivity is 45 associated with a significantly worse prognosis. HER2 first 46 became targetable in patients with trastuzumab (Herceptin, 47 ™ Genentech/Roche), a monoclonal antibody that has sig-48 nificantly improved outcomes for patients with HER2-49 positive BC, but the efficacy of trastuzumab is limited in 50 some patients by acquired and de novo resistance [2]. 51 HER family signalling 52There are 20 known RTK families: since members of over 53 half of these have been found to be mutated or overex-54 pressed in diseases marked by abnormal proliferation, 55 RTK's have been considered potential targets for cancer 56 therapy. HER2, a type 1 transmembrane protein RTK, and 57 an oncogenic driver of the growth of HER2-positive BC, is 58 associated with a shorter time to relapse and decreased 59 overall survival (OS 44Author Proof 26] evidence shows that lapatinib is effective against 151 trastuzumab-resistant HER2-positive BC, and it is cur-152 rently used as subsequent therapy for patients with disease 153 that has progressed on trastuzumab. Lapatinib inhibits 15...

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