One of the biggest challenges facing cancer research was aptly summarised by Levi Garraway and Pasi Jänne in this month’s Cancer Discovery journal:

“All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance.”

It will therefore come as no surprise to PSB readers that resistance occurs with two drugs approved by the FDA only last year; vemurafenib (BRAFV600E melanoma) and crizotinib (ALK+ lung cancer). We’ve discussed the development of resistance in melanoma here via several potential mechanisms in the past and potential strategies for overcoming them (eg MEK inhibitors), but what about lung cancer?

Two recently published papers have shed some new light on this topic. Doebele et al., (2012) and Katayama et al., (2012) both looked at mechanisms of resistance associated with ALK-rearranged lung cancers.

What did the research show?

Both of these papers were published in March, but in separate journals.

Doebele et al., (2012) examined mechanisms of ALK resistance in EML4-ALK–positive non-small cell lung cancer (NSCLC) patients who had progressed while on crizotinib patients (n=11). The essence of their findings were as follows:

  • Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. Two of the patients exhibited a novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro.
  • Two patients, including one with a resistance mutation, exhibited new onset ALK copy number gain (CNG).
  • One patient showed epidermal growth factor receptor (EGFR) mutant activity, without evidence of a persistent ALK gene rearrangement.
  • Two patients had a KRAS mutation, one of which occurred without evidence of persisting ALK gene rearrangement.
  • One patient showed the emergence of an ALK gene fusion–negative tumour with no identifiable alternate driver.
  • Two patients retained ALK positivity, with no identifiable resistance mechanism.

Meanwhile, Katayama et al., (2012) attempted to characterise acquired resistance, i.e. the adaptive resistance that occurs in response to treatment with a TKI. They also took biopsies from patients (n=18) with EML4-ALK–positive (NSCLC) patients who had progressed while on crizotinib. They found that in approximately a a quarter to a third of patients (22% to 36%) multiple mutations were found after sequencing of the ALK kinase domain exons. This resulted in amino-acid substitutions or insertions that are predicted to impair crizotinib binding. When this happens, the drug stops working and patients will relapse on therapy.

More specifically, there were:

  • Five patients (28%) had tumours with alterations in the ALK gene that were the underlying cause of the resistance.
  • There were four different somatic mutations within the ALK gene.
  • One case where the ALK gene was amplified.
  • One ALK mutation was highly resistant to all of the inhibitors examined.

In addition, they observed evidence of alternative mechanisms of resistance evolving, including activation of EGFR and KIT.

What do these results mean?

Firstly, it is striking that there are so many potential escape routes and mechanisms of adaptive resistance to crizotinib therapy.

Secondly, as Garraway and Jänne noted:

“Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer.”

However, while this is a true and accurate statement, I am left wondering how this might play out in clinical practice? By that, I mean how does a community medical oncologist, who sees the bulk of NSCLC patients go about incorporating this information? For now they can’t, as we are awaiting the results of numerous clinical trial readouts – hopefully there will be some at the annual ASCO meeting in June.

The sheer breadth of the heterogeneity also raises the issue of how will community doctors be able to process all this complex information and select patients for appropriate combination therapies based on numerous potential mechanisms of resistance. Biopsies aren’t always practical in these situations, but perhaps we may see the development of alternative methods of detection evolve in the future.

References:

rb2 large gray On adaptive mechanisms of crizotinib resistance in ALK positive lung cancerGarraway, L., & Janne, P. (2012). Circumventing Cancer Drug Resistance in the Era of Personalized Medicine Cancer Discovery, 2 (3), 214–226 DOI: 10.1158/2159–8290.CD–12–0012

Doebele, R., Pilling, A., Aisner, D., Kutateladze, T., Le, A., Weickhardt, A., Kondo, K., Linderman, D., Heasley, L., Franklin, W., Varella-Garcia, M., & Camidge, D. (2012). Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer Clinical Cancer Research, 18 (5), 1472–1482 DOI: 10.1158/1078–0432.CCR–11–2906

Katayama, R., Shaw, A., Khan, T., Mino-Kenudson, M., Solomon, B., Halmos, B., Jessop, N., Wain, J., Yeo, A., Benes, C., Drew, L., Saeh, J., Crosby, K., Sequist, L., Iafrate, A., & Engelman, J. (2012). Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers Science Translational Medicine, 4 (120), 120–120 DOI: 10.1126/scitranslmed.3003316