Resistance to receptor tyrosine kinase inhibitors in solid tumors: can we improve the cancer fighting strategy by blocking autophagy?

Abstract

A growing field of evidence suggests the involvement of oncogenic receptor tyrosine kinases (RTKs) in the transformation of malignant cells. Constitutive and abnormal activation of RTKs may occur in tumors either through hyperactivation of mutated RTKs or via functional upregulation by RTK-coding gene amplification. In several types of cancer prognosis and therapeutic responses were found to be associated with deregulated activation of one or more RTKs. Therefore, targeting various RTKs remains a significant challenge in the treatment of patients with diverse malignancies. However, a frequent issue with the use of RTK inhibitors is drug resistance. Autophagy activation during treatment with RTK inhibitors has been commonly observed as an obstacle to more efficacious therapy and has been associated with the limited efficacy of RTK inhibitors. In the present review, we discuss autophagy activation after the administration of RTK inhibitors and summarize the achievements of combination RTK/autophagy inhibitor therapy in overcoming the reported resistance to RTK inhibitors in a growing number of cancers.

Keywords: Autophagy; Combination treatment; Drug resistance; Receptor tyrosine kinase inhibitors.

Fig. 1

RTK activation in malignant cells and possibility for the combined therapy. a The constitutive, ligand-independent, catalytic activation of RTK under pathophysiological conditions leads to uncontrolled cell proliferation as well as increased cell survival and metastasis. b Blocking RTK function with inhibitors (orange blocks) activates a bypass mechanism that involves the induction of autophagy, which may contribute to the acquisition of drug resistance. c The enhanced efficacy of combination approaches (RTK inhibitors and autophagy inhibitors, such as chloroquine (CQ) or 3-methyladenine (3-MA); yellow blocks) with respect to a single RTK-targeted strategy suggests this method as more promising strategy for the elimination of tumor cells

Fig. 2

Potential molecular mechanism of autophagy induction in the presence of RTK inhibitors. One of the pathways through which autophagy could be induced after RTK inhibition is PI3K/AKT/mTOR, which, in addition to other roles, blocks the initiation of autophagy. The initial step of autophagy is regulated by the ULK kinase complex, which is comprised of ULK, ATG13, and FIP200. This step is followed by the alignment of additional proteins that form the Vps34 complex (Vps34, Beclin-1, and Atg14L), which is needed for phagophore creation. Afterwards, the phagophore progresses toward the autophagosome by recruiting other proteins (Atg12/Atg5/Atg16 and LC3) within the double-layered membrane. At this step, as the autophagosomal membrane is increasing in size, the cytosolic contents are engulfed, thereby filling up the autophagosome with degradable intracellular cargo. Completely matured autophagosomes then fuse to lysosomes, generating autolysosomes, which enables the degradation of the included cargo. In this way, diverse cellular molecules are recycled and made available for reuse by the cell. Additional bypass mechanisms that may lead to the induction of autophagy after the addition of RTK inhibitors are not excluded (interrupted arrow). Orange and yellow blocks represent RTK and inhibitors of autophagy, respectively