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Page 83 Giovannetti et al. Cancer Drug Resist 2018;1:82-6 I http://dx.doi.org/10.20517/cdr.2018.05

During the past two decades novel anticancer treatments have emerged from advances in our understanding
of tumor cell biology, and a number of molecular and biologic targets have been identified. New drugs have
been developed to attack these targets and their use to neutralize specific molecules or genes involved in the
development of cancer is appropriately called “targeted therapy”. The development of these novel molecularly
targeted agents responds to the fact that conventional chemotherapeutic treatments have reached an efficacy
plateau against most solid tumors, and deal with significant toxicity . Cytotoxic drugs inflict cell death by
[1]
affecting processes that are commonly overactive or enhanced in tumor compared with normal cells, such as
DNA synthesis. Biologic agents interact with receptors, ligands, signaling molecules, or genes that are pivotal
in tumor growth and development, and they can inhibit tumor cell proliferation, induce programmed cell
death, inhibit angiogenesis, or enhance antitumor immune response .
[2,3]
A number of targeted therapies are currently employed or being implemented for the treatment of different
hematologic and solid malignancies, such as imatinib, an inhibitor of the BCR-ABL tyrosine kinase for
the treatment of chronic myeloid leukemia , and the first-, second- and third-generation EGFR inhibitors
[4]
gefitinib, erlotinib, afatinib and osimetinib in non-small cell lung cancer (NSCLC) . Others are currently
[5]
being evaluated as both monotherapy and in combination with cytotoxic drugs or others targeted agents.

However, several clinical studies demonstrated that targeted therapy in combination with cytoreductive
chemotherapy should not be given to all patients irrespective of their characteristics, but only to individuals
presenting the molecular target of the therapy and in whom these targets are crucial for cancer cell survival .
[6]
Crizotinib clearly represents an example of a successful application of such straightforward development
from chemical identification of the active principle to the demonstration of its clinical activity and approval
for clinical use. From the very early stages during its development it was indeed evident that it would target
both c-Met and the EML4-ALK gene fusion product described in 5%-10% of NSCLC patients . This produced
[7]
accelerated clinical development in those patients and it took only three years to complete a phase III trial in
selected patients, achieving excellent results, and to obtain FDA registration.

A proper pharmacological evaluation should also be accompanied by a deeper understanding of the genetic
heterogeneity of most tumors, as detected using patient samples obtained during treatment and following
disease progression . Only then, these innovative therapeutic approaches are expected to improve the
[8]
efficacy and selectivity of current anticancer regimens.

Since the vast majority of advances in the treatment of cancer have resulted from the use of combination
therapy, another important issue is the correct development of combination of newer agents with
chemotherapy. Drug combinations are indeed widely used because multiple drugs affect multiple targets and
cell subpopulations, increasing the therapeutic effect and minimizing drug resistance, but in several cases
the addition of new targeted agents to standard regimens failed to improve survival [9,10] .

This outcome may be explained by the lack of patient selection as well as by other factors, including possible
negative interaction or suboptimal design of the studies, inaccurate evaluation of antitumor efficacy, and
controversies on drug combination analysis in preclinical models. Of note, only a few preclinical studies
predicted such disappointing outcomes , and further studies on potential molecular mechanisms
[11]
underlying the interaction between chemotherapy and are needed (as illustrated in the Figure 1 for the
preclinical data on combination of anti-EGFR agents and chemotherapeutic compunds). Cytotoxic agents
and EGFR inhibitors may interact through modulation of the main downstream signalling pathways
regulated by EGFR. The phosphorylation of EGFR occurs in response to several cytotoxic stresses including
various anticancer drugs (i.e. in a SRC-dependent manner after cisplatin) and correlates with the synergistic
inhibition of cell growth and induction of apoptosis by anti-EGFR agents . EGFR phosphorylation also
[12]