Actin expression may cause muscle spasms in cases of BCC treated with Hedgehog inhibitors

Actin expression may be the root of muscle spasms in patients with basal cell carcinoma who are treated with Hedgehog inhibitors, according to a study.

“Since the majority of cases of BCC demonstrate Hedgehog signaling hyperactivation, Hedgehog pathway inhibitors provide durable treatment options and improved clinical outcomes for patients with advanced BCC,” Natalie Teh, MD, and Liang Joo Leow, BA BSc, MBBS, MPH&TM, GradCertIT, FACD, FAAD, ACMS, of Sydney, Australia, wrote.

Among the most common adverse events associated with Hedgehog inhibitor therapy is muscle spasms, according to Teh and Leow. While conventional wisdom dictates that these events occur due to calcium inux into the muscle cells, they presented data for a case series of nine patients with advanced basal cell carcinoma (BCC) undergoing treatment with sonidegib that argues for an alternate etiology based on increased actin expression.

They described how muscle contraction is initiated by an impulse delivered to presynaptic nerve terminals. This, in turn, releases acetylcholine and activates “a muscle action potential via the postsynaptic receptors,” according to the findings.

At this point, the action potential releases calcium that binds to a regulatory protein and reacts with actin and myosin to shorten muscle fibers and cause a contraction.

While it is unclear how Hedgehog inhibitors may cause muscle spasms, Teh and Leow suggested that it is thought that noncanonical Smoothened activation promotes plasma membrane calcium channels to open.

The researchers propose an alternative etiology for this phenomenon. “The Hedgehog signaling pathway regulates E-cadherins and adherens junction protein expression, which is essential for maintaining the integrity of the actin cytoskeleton,” they wrote. “Actin, the main component in contractile microlaments, is crucial for cell mobility and transport.”

Other data have shown that 67% of micronodular BCCs, 62% of morpheaform BCCs and 0% of nodular BCCs show evidence of alpha-smooth muscle actin (alpha-SMA), a cytoskeletal protein isoform of actin,

With this in mind, previous data have shown micronodular BCCs demonstrate elevated alpha-SMA expression, which may be associated with deeper tissue and neural invasion. Moreover, expression of alpha-SMA within the stroma of BCC malignancies may indicate stromal myofibroblasts, which carry associations with both tissue invasion and aggressive tumor behavior, according to the findings.

“Myobroblasts play an essential role in cell contractility, modulating the formation of extracellular matrix and assembling bronectin — serving as a scaffold to bind collagen and other extracellular matrix proteins,” Teh and Leow wrote. In addition, myobroblast assembly of bronectin may have an impact on peripheral nuclear positioning of skeletal muscle cells.

All of this may result in muscle spasms in these patients, according to Teh and Leow.

“The Hedgehog signaling pathway appears to have a ow-on effect on muscle function through myobroblast alpha-SMA expression, with immunochemistry demonstrating a strong positivity of muscle-specic actin in BCCs,” the researchers wrote. “Accordingly, inhibition of the Hedgehog signaling pathway results in decreased E-cadherin expression and disassociation of the E-cadherin/beta-catenin protein complex — disrupting the actin cytoskeleton, destabilizing adherens junctions and inuencing myobroblast behavior.”