RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway–Dependent Tumors

Abstract

Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS/MAPK pathway circumvents Shh pathway-dependency, drives tumor growth and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together these findings reveal a critical role of RAS/MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.

Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4

“…These mutations reduce the affinity of drug:target interactions (9). Activating mutations in SUFU result in persistent SHH pathway signaling independent of Smo activity (12). To determine whether tumor regrowth in the GDC-0449 treatment group was the result of acquired mutations in murine Smo or Sufu , we sequenced the DNA encompassing the ligand-binding pocket region of the murine Smo gene and the entirety of murine Sufu following GDC-0449 treatment and tumor regrowth.…”

“…In other cases, genetic alterations in downstream components of the SHH pathway rendered tumor cell growth independent of Smo activity (11, 12). Still, in other cases, no Smo or SHH pathway component mutations were identified, and the basis for resistance remains undefined (6, 13).…”

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

“…We recently demonstrated that activation of the RAS/MAPK pathway can also cause resistance to Smo inhibitors by suppressing Shh signaling and shifting tumor cell dependence to Ras signaling (Zhao et al, 2015). RAS/MAPK-mediated resistance was characterized by increased metastatic potential of tumor cells.…”

Smoothened regulation in response to Hedgehog stimulation

“…However, cancer cells can acquire resistance and vismodegib becomes ineffective (Atwood et al, 2015; Sharpe et al, 2015). Several different mechanisms of resistance have been reported, including those through mutations in Smo (Wang et al, 2013), activation of Gli2 (Buonamici et al, 2010), mutations in the negative regulator Suppressor of fused (Sufu) (Kool et al, 2014), and activation of RAS/MAPK pathway (Zhao et al, 2015). Therefore, a better understanding the mechanisms of Smo regulation in the fundamental development processes is critical to developing more effective therapeutic treatments for cancers caused by Smo dysregulation.…”