Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy

Abstract

Cancer often arises when normal cellular growth goes awry due to defects in critical signal transduction pathways. A growing number of inhibitors that target specific components of these pathways are in clinical use, but the success of these agents has been limited by the resistance to inhibitor therapy that ultimately develops. Studies have now shown that cancer cells respond to chronic drug treatment by adapting their signaling circuitry, taking advantage of pathway redundancy and routes of feedback and cross-talk to maintain their function. This review focuses on the compensatory signaling mechanisms highlighted by the use of targeted inhibitors in cancer therapy.

Figure 1.

Oncogenic EGFR signaling. (A) Mutant EGFRs engage the Raf/MEK/ERK, PI3K/AKT/mTOR, and Src/STAT effector pathways to promote cell proliferation, cell survival, and tumor growth. Proteins targeted by inhibitor (I) therapy are indicated. (B) Signaling redundancy and cellular reprogramming can confer EGFR inhibitor resistance. In the case of signaling redundancy, increased signaling through other RTKs that activate the PI3K, ERK, and STAT pathways eliminates the consequence of EGFR inactivation. In cellular reprogramming, autocrine activation of the TGFβ receptor promotes a different cellular program, which releases the tumor cells from their dependency on EGFR activation.

Figure 2.

Regulatory circuits involving Src/SFKs. (A) SFKs are hyperactivated in multiple mechanisms of ErbB2 inhibitor (T1, trastuzamab) resistance and can mediate a positive feedback loop promoting RTK dimerization and signaling. Ligand engagement of the EPO receptor also activates Src/SFKs via the JAK2 kinase. In addition, the reciprocal regulatory relationship between SFKs and PTEN is indicated. Dephosphorylation of SFKs by PTEN's protein phosphatase activity inactivates the SFKs, whereas phosphorylation of PTEN induced by SFKs inhibits the function of PTEN. (B) JAK2 reactivates STAT3 in response to SFK inhibition via a signaling circuit involving the STAT5A and SOCS2 proteins.

Figure 3.

Feedback inhibition mediated by the PI3K/AKT/mTOR pathway. Pathway cross-talk and inhibitory feedback circuits induced by activated components of the PI3K/AKT/mTOR pathway are shown. Pathway connections that represent mechanisms of negative feedback are denoted by a red line. Disruption of the feedback circuits by inhibitor treatment can alter the effectiveness of drug therapy. Transcriptional events that occur downstream from S6K and FOXO are also indicated.

Figure 4.

Mechanisms of Raf inhibitor resistance. Raf inhibitor resistance can occur through mechanisms that reactivate ERK signaling, including activating Ras mutations (1), increased Raf expression (2), truncation of V600E-B-Raf (3), increased Cot1 expression (4), and activating MEK mutation (5). Activation of compensatory pathways, such as up-regulated PDGFR (6) and IGF-1R signaling (7), can also confer Raf inhibitor resistance.