Abstract The development of protein kinase inhibitors (PKIs) has revolutionized the treatment of cancer. As of August 2019, 45 PKIs have been approved by the FDA for the treatment of a wide range of human malignancies including, but not limited to: AML (n=2), breast cancer (n=5), non-small cell lung cancer (n=11), CML (n=5), CLL (n=1), colorectal cancer (n=1), GI stromal tumor (n=3), hepatocellular carcinoma (n=3), mantle cell lymphoma (n=2), melanoma (n=6), non-small cell lung cancer (n= 10), renal cell carcinoma (n=6), soft tissue sarcoma (n=3, excluding GIST approved agents), thyroid cancer (n=4), and urothelial cancer (n=1). In addition to the above approved agents, dozens of other PKIs have been tested in clinical studies but lacked sufficient clinical activity to warrant further clinical development. In analyzing the historical development of PKIs, certain characteristics of the targeted disease are predictive for successful PKI drug development. First, genomic abnormalities involving the target of interest, such as gain-of-function mutations or amplification, are more likely to be predictive of a successful drug development strategy than assessment of target protein expression levels (e.g. targeting EGFR in NSCLC). Second, targeting mutant protein kinases that are known to be critical to tumor initiation and/or early tumor progression stages is much more likely to be effective than targeting mutant PKIs that develop late in the progression to advanced malignancy (e.g. BCR-ABL in CML). Third, addiction of the tumor to the protein kinase of interest with a limited ability to substitute an alternative oncogenic mechanism is highly predictive of a successful PKI targeting approach. This is often indicated clinically by the acquisition of secondary mutations in the targeted kinase in drug-resistant tumor clones. Finally, targeting another critical signaling pathway to achieve an additive or synergistic effect can sometimes significantly increase the clinical activity of a PKI (e.g. combining BRAF and MEK inhibitors to treat BRAF-mutant melanoma). Despite the significant, and in some cases transformative activity of these PKIs in the treatment of advanced cancer, the clinical usefulness of these agents is eventually lost due to the development of drug-resistant tumor clones. To date, multiple mechanisms have been reported to result in PKI-resistance, with different mechanisms being more often associated with specific PKIs and cancer types. These mechanisms include: 1) mutation of the target protein (e.g. KIT in GI stromal tumor); 2) re-wiring of signaling to bypass the targeted protein without additional oncogenic mutations (e.g. BRAF in melanoma); 3) the acquisition of oncogenic mutations of an alternative kinase that allow re-activation of signaling downstream of the targeted pathway (e.g. RAS mutations in NTRK translocated tumors treated with NTRK PKIs); 4) de-differentiation to a more primitive cell phenotype that is no longer dependent upon the originally targeted kinase (e.g. breast cancer); and 5) cellular epithelial to mesenchymal transformation (EMT) which can substitute a different pattern of survival signaling compared with the epithelial cellular phenotype (e.g. NSCLC treated with EGFR inhibitors). The complexity of overcoming secondary PKI drug resistance is further complicated by tumor heterogeneity and the variation in resistance mechanisms used by different tumor clones. However, understanding the particular resistance mechanisms involved in clinical drug resistance has led to the development of improved next generation PKIs. In addition, more recently it has become possible to combine PKIs with other small molecule inhibitors or entirely different classes of anti-cancer agents, including monoclonal antibodies, hormonal treatments, and immunotherapy agents. Based on these results, more potent and selective PKIs will continue to be developed to be used in monotherapy and combination treatment approaches. In addition, therapeutic strategies that include immunotherapy agents and/or EMT-directed treatments have the intriguing potential to even more radically alter the treatment paradigm for advanced cancer, leading to a significant improvement in survival for patients with advanced cancer. Citation Format: Michael Heinrich. Targeted therapy with protein kinase inhibitors Lessons learned from the last 20 years [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr ED01-03. doi:10.1158/1535-7163.TARG-19-ED01-03
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Jan 16, 2022
Dan Wang + 4
