LK or IGF1R: When selectivity hurts

success of small molecule tyrosine kinase (TKI) inhibitors in cancer treatment and recent studies both in vitro and in vivo sparked interest in targeting the insulin-like growth factor receptor 1 (IGF1R). The development of several antibodies as well as small molecule inhibitors aimed at this receptor continues to be the subject of numerous preclinical studies and clinical trials. IGF1R, a tyrosine kinase receptor, regulates growth and metabolism, and is also associated with signaling in aging and disease. In cancer, IGF1R plays a role in cancer cell mobility and metastasis. There are three ligands for the cell surface receptor—insulin-like growth factor 1 (IGF-1), IGF-2 and insulin. Reduced activity of IGF-1 together with reduced activity of growth hormone lead to prolonged life span and protection from age-related damage and diseases, including cancer and diabetes, making inhibition of these pathways a promising target for anti-aging therapies [1]. IGF1R shares high homology with the insulin receptor (IR), making the design of selective small molecule inhibitors difficult. Thus, monoclonal antibodies were developed first to achieve high selectivity for IGF1R and no cross-reactivity with the insulin receptor to avoid problems with metabolic inhibition and insulin resistance. However, the results of the first clinical trials were underwhelming, with little objective responses or clinical benefit, except in selected patients whose tumors harbored well defined, but rare gene fusions [2]. This may be attributed to the ability of cancer cells to circumvent the IGF1R signaling via the insulin receptor, and the fact that most patients entering clinical trials have heavily pre-treated tumors with potentially altered expression of IGF1R. In fact, inhibition of IGF1R may lead to increased IGF-1, which results in enhanced insulin receptor signaling that in turn drives tumor growth [3]. In addition, the IGF1R and IR form complex multi-subunit structures that exist as dimers and assemble as combinations of IGF1R and IR subunits (heterodimers) or IGF1R-IGF1R and IR-IR (homo-dimers). The antibodies inhibit only the set of IGF1R-IGF1R homodimers, allowing the signaling to continue via the heterodimer and IR-IR homodimer. Editorial Does this mean that inhibition of both receptors is better? Small molecule TKIs inhibit both IGF1R and IR, including heterodimer and IR-IR homodimer conformations. We conducted a phase I trial of OSI-906 (linsitinib), an IGF1R TKI, in patients with advanced solid tumors [4]. The drug was well tolerated when administered by once-daily or twice-daily continuous dosing schedule and resulted in decreased phosphorylation of IGF1R and IR in …