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Understanding Resistance to ALK Inhibitor Therapy

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Understanding Resistance to ALK Inhibitor Therapy: Repeat Biopsies Provide New Insights

http://blog.lungevity.org/2012/01/13/me ... alk-inhib/

January 13th, 2012 - by Dr. Jack West

The lung cancer group at the University of Colorado has just published a manuscript in Clinical Cancer Research evaluating the molecular mechanisms of resistance to the ALK inhibitor crizotinib (XALKORI) in patients with an ALK rearrangement. They collected tissue from 14 patients with an ALK rearrangement who were either resistant from the start (2 patients) or became resistant after a period of effective treatment with crizotinib (the other 12), of whom 11 had evaluable tumor tissue. Their goal from this work was to determine whether the ALK rearrangement remained present, whether additional copies of the ALK gene were now detectable, or whether new mutations may have emerged as an alternative oncogenic (cancer-inducing) driver of the cancer.

From the 11 patients who were the subject of the final work, they detected a wide range of apparent mechanisms of progression. Four (36%) had new, separate mutations in the ALK gene that were now associated with resistance; two cases had a particular mutation (known as G1269A) that has been found to confer resistance to crizotinib in preclinical lab work. Another two patients (18%), one with and one without an ALK resistance mutation, had developed additional copies of the ALK gene, which could presumably overcome the effects of an ALK inhibitor like crizotinib. Another three (27%) no longer had a detectable ALK rearrangement in their tumor tissue; one had developed a new EGFR mutation, one had a new KRAS mutation, and one had an unknown mutation (the investigators had tested for a limited panel of known high yield ones). Another patient (9%) now had a KRAS mutation but ALSO continued to have an ALK rearrangement present. The final two still had an ALK rearrangement but no detectable mutation or other changes that the authors felt would explain the development of resistance. The summary of the distribution of findings is shown in the pie chart to the left in the figure below:

(Click on blog link above to view image)

The right side of the figure (B), illustrates two potential mechanisms for acquired resistance. The first is the development of a second cancer driver that is actually present, coexisting in the cancer cell with the mutation in question (the left panel of figure B), such as development of c-MET over-expression in EGFR mutation positive cancer cells. Under evolutionary pressure of a treatment with an EGFR tyrosine kinase inhibitor (TKI), the cancer cells still have the driver mutation (EGFR, in this example) but develop a competing and overriding feature that confers resistance.

A few of the patients in this paper also highlight that it is possible for the selection pressure of effective treatment to lead to a predominance of a new and separate oncogenic driver mutation (right panel of part B in the figure). The idea here is that there are different subsets of cancer cells. For instance, prior to treatment with a targeted therapy the cancer may be comprised of primarily ALK-positive cancer cells, while a small minority has a KRAS mutation. After ALK inhibitor therapy, however, those ALK positive cells die, yielding a cancer that is now growing and comprised predominantly of KRAS mutation positive cells.

There is a lot of clinical relevance to this early work, even if the implications remain unproven. First, there appears to be a potentially significant value to doing repeat biopsies, at least in those patients who have shown a very good response to targeted agents and/or have an identified mutation, since the biopsy results may help shape subsequent treatment decisions. We see that it is possible, albeit rare, for a person to have a new EGFR mutation after treatment with an ALK inhibitor, for example, that could lead to effective treatment with an EGFR TKI. Moreover, the finding that in some patients, the cancer cells no longer have an ALK rearrangement suggests that these patients won’t benefit from a different ALK inhibitor or treatment with a heat shock protein inhibitor (a class of investigational agents that have also emerged as very promising for ALK positive patients).

We know that the cancer, or at least some areas of the cancer, can transition into a new version, sometimes a different subtype of lung cancer entirely. Even looking at the small number of cases here, we can see a complex array of possibilities. Our understanding of what is possible is changing almost with each new case, and this work is helping direct us to literally individualized recommendations for patients.

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