Targeted therapies in cancer and mechanisms of resistance

Abstract

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy, which acts on all dividing cells, targeted drugs allow to hit subpopulations of cells directly involved in tumor progression in a more specific manner [1]. The frequent alteration of receptor tyrosine kinases (RTK) in human malignancies led them to be considered as targets for anti-neoplastic therapies; this resulted in the development of several inhibitors that have shown a strong clinical activity [2]. The concept of “oncogene addiction” has added further rationale to the use of targeted therapies [3]. Even if the recent introduction in cancer therapy of several selective tyrosine kinase inhibitors has had a dramatic effect in oncology, after the first excitement following the initial results, the clinicians had to face soon the problem of primary and secondary resistance to treatment: a percentage of patients expressing the target in their tumors does not respond to the treatment (primary or “de novo” resistance), while in most of the responders, the treatment is quite rapidly no longer effective (secondary or “acquired” resistance) (Fig. 1) [4]. Therefore currently, the main challenges associated to targeted therapies are the relatively small proportion of patients that can benefit from these treatments and the almost inevitable occurrence of resistance. Thus, the identification of predictive biomarkers of resistance and the understanding of the resistance mechanisms are mandatory to improve the efficacy of these therapies. Genetic studies have recently highlighted the high level of heterogeneity in tumors, where many clones with different genetic features coexist. Cancers, in fact, evolve through a series of waves of clonal growth where single clones acquire genetic alterations conferring differential fitness [5]. Moreover, environmental factors (such as secretion of cytokines by the stromal cells or the availability of nutrients and oxygen) can favor the onset and permanence of such different cell populations. In this scenario, exposing a tumor to a targeted therapy can abruptly subvert the equilibrium that allows the coexistence of these cell populations. A paradigmatic example is represented by lung cancers displaying activating epidermal growth factor receptor (EGFR) mutations that render them responsive to EGFR inhibitors. Treatment with EGFR inhibitors, in fact, results in massive death of EGFR-addicted cancer cells, thus profoundly impacting on the overall architecture of the tumor. Cells that are not responsive to the inhibitor (such as those harboring the “resistant” EGFR mutation T790M) preexist inside the tumor and can outgrow under the selective pressure imposed by the drug [6, 7]. So, a cell population present in the primary cancer at low frequency due to a decreased fitness compared to cells devoid of the mutation becomes enriched over time and can reconstitute the tumor, leading to relapse (Fig. 1). Thus, from the beginning, the tumor contains cells harboring genetic lesions that can sustain resistance to targeted therapies. As mentioned by Dr. Vogelstein in a recent paper, “resistance is a fait accompli and the time to recurrence is simply the interval required for the subclone to repopulate the lesion” [8]. The presence of genetic heterogeneity in the primary tumor may also explain the common finding of patients presenting, at relapse, different metastases, each bearing a diverse genetic alteration responsible for drug resistance. The knowledge of the existence in primary tumors of cell subpopulations harboring genetic alterations leading to drug resistance has induced researchers and clinicians to test the efficacy of combination therapies in S. Corso : S. Giordano (*) Department of Oncology, University of Torino, Strada Provinciale 142, Candiolo, Torino 10060, Italy e-mail: silvia.giordano@ircc.it