Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy

Abstract

Targeted therapies such as kinase inhibitors and monoclonal antibodies have dramatically altered cancer care in recent decades. Although these targeted therapies have improved patient outcomes in several cancer types, resistance ultimately develops to these agents. One potential strategy proposed to overcome acquired resistance involves taking repeat tumor biopsies at the time of disease progression, to identify the specific molecular mechanism driving resistance in an individual patient and to select a new agent or combination of agents capable of surmounting that specific resistance mechanism. However, recent studies sampling multiple metastatic lesions upon acquired resistance, or employing "liquid biopsy" analyses of circulating tumor DNA, have revealed that multiple, heterogeneous resistance mechanisms can emerge in distinct tumor subclones in the same patient. This heterogeneity represents a major clinical challenge for devising therapeutic strategies to overcome resistance. In many cancers, multiple drug resistance mechanisms often converge to reactivate the original pathway targeted by the drug. This convergent evolution creates an opportunity to target a common signaling node to overcome resistance. Furthermore, integration of liquid biopsy approaches into clinical practice may allow real-time monitoring of emerging resistance alterations, allowing intervention prior to standard detection of radiographic progression. In this review, we discuss recent advances in understanding tumor heterogeneity and resistance to targeted therapies, focusing on combination kinase inhibitors, and we discuss approaches to address these issues in the clinic.

Fig. 1

Agents used for targeted cancer therapy. This figure details the agents discussed in this review, including monoclonal antibodies and kinase inhibitors targeting multiple receptors, including MET, FGFR (fibroblast growth factor receptor), HER2 (human epidermal growth factor receptor 2), EGFR (epidermal growth factor receptor), and ALK (anaplastic lymphoma kinase). Additionally, kinase and phosphatase inhibitors targeting downstream effectors of these receptors are indicated, including SHP2 and members of the PI3K (phosphatidylinositol-3-kinase) and MAPK (mitogen-activated protein kinase) pathways. Lastly, monoclonal antibodies targeting receptors regulating immune response, PD-1 and PD-L1, are also discussed

Fig. 2

Heterogeneity and clinical resistance to targeted therapy. Genetic heterogeneity in human tumors can result in multiple outcomes for clinical responses to targeted therapy. In each case, monitoring tumor dynamics by analysis of liquid biopsies may improve clinical interventions. a A targetable genetic alteration (gray) may be present in most tumor cells, but may occur concurrently with resistance-driving mutations. This leads to upfront resistance despite the presence of the targetable alteration. b A targetable genetic alteration may only be present in a minority of tumor cells. In this case, the majority of cells in a particular tumor will exhibit upfront resistance. c Acquired resistance occurs when resistant subclones are selected from a heterogeneous tumor. Geographical resistance occurs when tumors are geographically heterogeneous and exhibit different genetic alterations at different tumor sites. In this case, each tumor will respond differently to targeted therapy

Fig. 3

Sequential targeted therapy assessed by longitudinal liquid biopsy. At the beginning of targeted therapy, all cells in the patient’s tumor possess an actionable genetic alteration (gray). The first treatment administered targets this first alteration. Liquid biopsy analysis demonstrates an initial decrease in the target alteration during treatment 1, yet reveals the outgrowth of an alteration causing resistance to treatment 1 (red). The red subclone can be targeted with treatment 2, where liquid biopsy analysis reveals a decrease in the frequency of resistance alteration 1. During this time, however, a third genetic alteration (blue) increases in frequency. This third mutation is resistant to treatment 2, yet is sensitive to treatment 3. During treatment 3, the frequency of the blue clone decreases, while residual clones harboring the first resistance mutation (red) may persist