Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

Abstract

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

PKB/Akt-dependent regulation of inflammation in cancer

“…These orchestrated signaling networks contribute to meet the increased metabolic demand of cancer cells, to promote uncontrolled proliferation and survival, and stimulate migration/invasion. Consistent with the cellular functions regulated by PKB, its hyperactivation is observed predominantly in poorly differentiated tumors that are invasive, fast growing, and resistant to treatment and correlated clinically with poorer outcomes [30].…”

Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights

“…The upstream triggers include activating mutations on NRAS, as well as amplification or alternative splicing of the mutated BRAF gene. Downstream reactivation of the MAPK pathway through activating mutations on MEK proteins has also been documented 91 . Re-dimerization of the kinase-dead form of mutant BRAF with endogenous CRAF, unfavourable disruption of the ERKdependent negative feedback signaling loop, upregulation of other pro-oncogenic molecules, such as RTKs , RTK ligands like HGF and COT have also been described 91 .…”

“…Downstream reactivation of the MAPK pathway through activating mutations on MEK proteins has also been documented 91 . Re-dimerization of the kinase-dead form of mutant BRAF with endogenous CRAF, unfavourable disruption of the ERKdependent negative feedback signaling loop, upregulation of other pro-oncogenic molecules, such as RTKs , RTK ligands like HGF and COT have also been described 91 . All of these mechanisms ultimately trigger the reactivation of MAPK and PI3K/Akt signaling that, in turn, drive melanoma cell survival.…”

Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells

“…The emergence of drug resistance mainly arises from the overexpression of membrane proteins that activate the efflux pump, thereby exporting drugs before they reach their intracellular sites of action. [3][4][5] Pgp, a typical drug-efflux transporter, has received increasing attention, Accordingly, considerable efforts have been focused on inhibiting the function of Pgp and ultimately increasing intracellular accumulation of drugs. 7 Previous studies have reported various inhibitors that were designed to block Pgp activity.…”