Adaptive stress signaling in targeted cancer therapy resistance

Abstract

The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. Although substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumo r cell survival during treatment and the development of resistance. Here we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize or eliminate targeted therapy resistance, thereby unleashing the full potential of targeted therapies to transform many cancers from lethal to chronic or curable conditions.

Figure 1. Oncogenic signaling in tumor cells

Shown are major signaling pathways involved in the initiation and progression of many tumors. Pathway crosstalk can occur at multiple levels from signaling emanating from the plasma membrane to the mitochondrial and nuclear events. Thus, there is significant potential for stress response signaling such that inhibition of one pathway results in the engagement of a distinct pathway that maintains tumor cell homeostasis and promotes escape from therapy. This profound robustness is a critical feature of the evolution of tumors both in the absence and the presence of therapy, consistently enhancing tumor survival in response to various stresses. Abbreviations: Raf, Raf proto-oncogene serine/threonine kinase; Mek, mitogen activated protein kinase kinase; Erk, extracellular signal related kinase; PI3K, phosphoinositide 3-kinase; AKT, v-akt murine thymoma viral oncogene homolog; IRS1, insulin receptor substrate; mTORC1/2, mammalian target of rapamycin; GRB2, growth factor receptor-bound protein; SOS, son of sevenless homolog; PTEN, phosphatase and tensin homolog; PDPK1, 3-phosphoinositide dependent protein kinase 1, TSC1/2, tuberus sclerosis; PLC, phospholipase C; RalGDS, ral guanine nucleotide dissociation stimulator; IKKα/β, inhibitor of nuclear factor kappa-B kinase subunit alpha/beta. NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells

Figure 2. Model for blocking primary and adaptive molecular events underpinning tumor cell survival in order to induce profound and durable responses in patients

Ligand stimulation, mutation, amplification or crosstalk between receptor tyrosine kinases (RTK1, RTK2) leads to their constitutive activation, which in turn activates downstream effector pathways. Inhibition of the driver oncogene leads to an immediate, adaptive stress response. Subsequently, signaling pathways are rewired in order to adapt to the new condition in which signaling from the oncogene is inhibited and sustain cell proliferation and survival. A new paradigm for cancer treatment would be the use of upfront combination therapies along with the oncogenic driver inhibition. While Drug A is normally used for inhibition of the driver oncogene, Drug B or Drug C can be used in combination upfront to prevent cancer cell adaptation. The outcome of this combination therapy approach would be enhanced killing of tumor cells and delay or prevention of therapy resistance. Abbreviations: Raf, Raf proto-oncogene serine/threonine kinase; Mek, mitogen activated protein kinase kinase; Erk, extracellular signal related kinase; PI3K, phosphoinositide 3-kinase; AKT, v-akt murine thymoma viral oncogene homolog; mTORC1/2, mammalian target of rapamycin; PLC, phospholipase C; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells