Understanding Resistance to Targeted Anticancer Therapies

Abstract

Cancer therapeutic regimens are gradually changing from using relatively unspecific cytotoxic agents to selective, pathway-centered approaches. The mechanistic rationale of targeted approaches is to destruct the tumor by blocking aberrant cell signaling, crucial for tumor maintenance and growth, but dispensable for healthy tissues. However, despite impressive initial responses in some patients, resistance to single-agent targeted therapies emerges almost invariably. Abrupt inhibition of an oncogenic signal sustaining tumor survival can cause initial drug responsiveness, but elaborate regulatory mechanisms safeguarding cellular homeostasis are often activated, resulting in drug resistance. Using RNA interference-based functional genetic screen, we investigated resistance mechanisms of cancer to targeted agents against RTK signaling pathways. These mechanistic insights led to the discovery of combinatorial strategies that are particularly powerful in overcoming drug resistance.

We solved a clinical enigma: why is BRAF mutant colorectal cancer (CRC) intrinsically resistant to BRAF inhibitors while melanomas carrying the same mutation are highly responsive? Inhibition of BRAF in colon cancer causes a rapid feedback activation of EGFR. Concomitant targeting EGFR and BRAF synergistically induces apoptosis and suppresses tumor growth in BRAF mutant CRC. The differential responses of CRC and melanoma to BRAF inhibitors can be attributed to the fact that EGFR is highly expressed in many CRC, but rarely in melanoma. However, we found melanoma can upregulate EGFR expression during the development of drug resistance. Mechanistically, we show that SOX10 loss triggers TGF β signaling, which in turn induces EGFR and PDGFRB expression. Surprisingly, upregulation of RTKs in BRAF mutant melanoma induces a state of oncogene-induced senescence in the absence of BRAF or MEK inhibitor treatment, while it confers a growth advantage in the presence of the drug. This notion potentially explains why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’. Increased RTK expression in drug-resistant tumors can be a biomarker to identify patients that may benefit from retreatment after a drug holiday.

Moreover, a different feedback loop is identified in KRAS mutant cancer when the same pathway is targeted as that in BRAF mutant colon cancer. We find intrinsic resistance of KRAS mutant lung and colon cancer to MEK inhibitors results from a MYC-dependent transcriptional upregulation of ERBB3. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the pro-apoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to the combinatorial treatment. Besides, we found that RAF1 suppression is also synthetic lethal with MEK inhibitors in KRAS mutant cancer. MEK inhibition induces RAS-dependent BRAF-RAF1 dimerization, which sustains MEK-ERK signaling. Prolonged dual blockade of RAF and MEK leads to persistent ERK suppression and efficiently induces apoptosis.

Besides we also discovered a mechanism by which SWI/SNF complex modulates drug responses in NSCLCs with MET amplification or ALK translocation.

These studies to date have given rise to five clinical studies with combinations of cancer drugs. Some of these studies have already shown promising results.