Theoretically the majority of resistance mechanisms

Theoretically, the majority of resistance mechanisms identified so far could be targeted by compounds that are already available, such as inhibitors of ER, PIK3CA/mTOR or FGFR1. However, the potential therapeutic advantage of combining these agents with standard HER2-targeting treatments must be weighed against the risk of causing toxicities. Moreover, the co-existence of different resistance mechanisms, as a result of intralesion or interlesion heterogeneity, may prevent the possibility to contemporaneously target all resistant tumor clones, as previously shown in other neoplasms (Pietrantonio et al., 2017). Optimizing methods to contemporaneously and reliably detect cell clones bearing different alterations associated with resistance, such as the analysis of circulating tumor DNA or circulating tumor cells, will be crucial to design treatments that are able to target the most relevant mechanisms in individual patients. Experimental strategies that are under investigation to improve the efficacy of current anti-HER2 treatments are summarized in Table 3. They include: 1) more potent anti-HER2 MoAbs, TKIs or ADCs; 2) new anti-HER2 combinations, including new TKIs (i.e. neratinib, tucatinib, poziotinib) plus T, P or T-DM1; 3) therapies aimed at enhancing antitumor immune responses; 4) targeting pathways downstream of HER2, such as PI3K or CDK4/6; 5) inhibition of crucial metabolic enzymes associated with T resistance, such as FASN; 6) the design of rational treatment sequences that alternate anti-HER2 MoAbs, which deplete HER2 on tumor cell membranes, with anti-HER2 TKIs, which stimulate HER2 exposure, possibly re-sensitizing Angiotensin 1/2 (1-7) amide australia to anti-HER2 MoAbs (Vici et al., 2017; Scaltriti et al., 2009; Fabi et al., 2017).
Conflict of interest statement Claudio Vernieri has no conflict of interest to declare Monica Milano has no conflict of interest to declare Marta Brambilla has no conflict of interest to declare Alessia Mennitto has no conflict of interest to declare Claudia Maggi has no conflict of interest to declare Maria Silvia Cona has no conflict of interest to declare Michele Prisciandaro has no conflict of interest to declare Chiara Fabbroni has no conflict of interest to declare Luigi Celio has no conflict of interest to declare Gabriella Mariani has no conflict of interest to declare Giulia Bianchi has no conflict of interest to declare Giuseppe Capri has no conflict of interest to declare Filippo de Braud has no conflict of interest to declare
Introduction Over the past decade, genomic profiling has enabled the identification of numerous actionable oncogenic drivers that are causative for cancer initiation and progression in multiple tumor types (Kandoth et al., 2013; Cancer Genome Atlas Research et al., 2013; Bailey et al., 2018). The same oncogenic drivers can promote the development and the growth of tumors with different histologies (Bailey et al., 2018). This observation has provided the rationale for the design of “basket trials”, in which the efficacy of a specific targeted therapy is tested against tumors that harbor the qualifying genomic aberrations, independent of tumor histology. Basket trials have been proven to be a particularly suitable approach when the targeted genomic alterations are rare driver events and occur across different cancer types (Hainsworth et al., 2018; Hyman et al., 2015). In this setting, even if the pharmacological target is present in small percentages of patients, the studies allow the rapid enrolment of a sufficient number of patients to evaluate the efficacy of the tested drug. Responses to therapy can be either tissue agnostic or histology-dependent. As an example of the former, objective clinical responses were obtained in up to 80% of patients with adult and pediatric tumors of different origin harboring oncogenic fusions involving the neurotrophin receptors tyrosine kinase genes NTRK1, NTRK2 or NTRK3 (encoding TRKA, TRKB and TRKC, respectively) treated with the TRK inhibitor Larotrectinib (Drilon et al., 2018). By contrast, the efficacy of the irreversible pan-ERBB inhibitor Neratinib against tumors harboring activating mutations in erbB2, the gene encoding for the human epidermal growth factor receptor 2 (HER2), has been shown to be largely dependent on tumor histology, with clinical responses achieved in breast, cervical and biliary cancer and intrinsic refractoriness in all the other tumor types tested including colorectal, bladder and ovarian cancer (Hyman et al., 2018).